Increased postoperative blood loss after cardiac operations

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1 Efficacy of Aprotinin, Epsilon Aminocaproic Acid, or Combination in Cyanotic Heart Disease Sandeep Chauhan, MD, Bisoi Akshay Kumar, MCh, Beeraka Heramba Rao, MD, Marigaddi Sanjeeva Rao, MCh, Bharat Dubey, MCh, Nita Saxena, MD, and Panangipalli Venugopal, MCh Cardiothoracic Centre, All India Institute of Medical Sciences, New Delhi, India Background. Aprotinin and epsilon aminocaproic acid are antifibrinolytic agents used to reduce postoperative blood loss after cardiopulmonary bypass. We compared low dose aprotinin with epsilon aminocaproic acid and a combination of the two agents to reduce postoperative blood loss in infants with congenital cyanotic heart disease undergoing corrective surgical procedures. Methods. This prospective study was conducted randomly on 300 children. acted as the control and did not receive either of the study drugs. received low dose aprotinin, group III received epsilon aminocaproic acid, and group IV received a combination of the two antifibrinolytic agents. Results. The control group had the longest time for sternal closure, maximum blood loss at 24 hours, and greatest requirements for packed red blood cells and platelets. Fibrinogen levels were significantly lower, and levels of fibrin breakdown products were significantly higher compared with the groups given either or both of the antifibrinolytics. Conclusions. Epsilon aminocaproic acid is as efficacious as low dose aprotinin in reducing postoperative blood loss and packed red blood cell and platelet requirements in children with congenital cyanotic heart disease. The combination of the two was slightly more effective. (Ann Thorac Surg 2000;70: ) 2000 by The Society of Thoracic Surgeons Increased postoperative blood loss after cardiac operations is a common problem [1] and is even more so after operations for cyanotic congenital heart disease. The increased incidence of postoperative bleeding in this group of patients has been proposed to result from preexisting coagulation disorders, platelet dysfunction, or reduced platelets and increased fibrinolysis [2], apart from the effects of cardiopulmonary bypass (CPB) such as dilutional reduction in coagulation factors from the effects of pump prime, the effects of CPB resulting in complement, platelet, and neutrophil activation, and the results of systemic heparinization [3]. Prophylactic use of antifibrinolytics to reduce postoperative blood loss from CPB-induced fibrinolysis has been in vogue for several years [4]. Aprotinin, a polypeptide of bovine origin, has been in clinical use for quite some time now to reduce blood loss after cardiac operations in both adults [5] and children [6]. Aprotinin is a nonspecific serine protease inhibitor that inhibits various proteases involved in coagulation and fibrinolytic and complement cascades. Low dose aprotinin is believed to inhibit plasmin and also protect platelet glycoprotein Ib receptors, which are responsible for platelet adhesion and are damaged by plasmin Accepted for publication April 21, Address reprint requests to Dr Chauhan, Department of Cardiac Anaesthesia, Cardiothoracic Centre, All India Institute of Medical Sciences, New Delhi , India; sancha@medinst.ernet.in. during CPB [7]. Epsilon aminocaproic acid (EACA) is a synthetic antifibrinolytic agent used to prevent primary and secondary fibrinolysis and to reduce postoperative blood loss after cardiac operations. EACA has been used extensively in adult patients undergoing a variety of cardiac operations [8, 9]. Use of EACA in children with cyanotic congenital heart disease was described by Gralnick [10] in 1970 in 2 children undergoing corrective surgical procedures in which preoperative use of EACA was found beneficial in reducing postoperative blood loss. Mc Lure and Izsak [11] studied the use of EACA to reduce bleeding during bypass in 25 of a total of 71 children undergoing open heart operations. EACA was found to be more effective in reducing blood loss in the 12 children with congenital cyanotic heart disease. Large studies on the use of EACA in children with cyanotic congenital heart disease are lacking. The primary mechanism of action of EACA is by inhibition of plasminogen activator substances and to a lesser degree through antiplasmin activity. Aprotinin acts primarily by inhibiting plasmin and kallikrein. Theoretically the actions of both these antifibrinolytics are complementary. We compared the relative efficacy of low dose aprotinin, EACA, and their combination to see if this translated clinically into more efficacious reduction in postoperative blood loss in children with congenital cyanotic heart disease undergoing corrective surgical procedures by The Society of Thoracic Surgeons /00/$20.00 Published by Elsevier Science Inc PII S (00)

2 Ann Thorac Surg CHAUHAN ET AL 2000;70: APROTININ, EACA, AND MIXTURE COMPARED 1309 Table 1. Demographic Data a Demographic Data Age (y), range 2.5 mo to 13 y 3 mo to 12.5 y 2.7 mo to 13 y 2.5 mo to 14 y Age (y), mean M/F 47/33 61/39 28/32 30/30 Weight (kg) BSA (m 2 ) There were no significant differences. BSA body surface area; M/F male/female. Material and Methods After receiving approval from the institute ethics committee and taking informed consent from the children s parents, we prospectively studied 300 consecutive children with congenital cyanotic heart disease (January 1997 to March 1999) scheduled to undergo a variety of corrective cardiac procedures with CPB. Patients taking aspirin, dipyridamole, or other anticoagulants or those with a known metabolic disorder, sepsis, renal failure, or previous exposure to aprotinin were not included in the study. Patients undergoing resternotomy are given high dose aprotinin as a matter of institute policy and so were not included in this study. Children who had undergone a previous shunt procedure through a lateral thoracotomy were included. The children were randomly allocated to one of four groups by having the child s attendant pick an unmarked envelope containing the group number. acted as the control group and were not given any study drug. received 10,000 KIU/kg aprotinin after anesthetic induction, 10,000 KIU/kg in the CPB pump prime, and 10,000 KIU/h for 3 hours after weaning from CPB. were given 100 mg/kg EACA after anesthetic induction, 100 mg/kg in the CPB pump prime, and 100 mg/kg on weaning from CPB over 3 hours. Patients in were given a mixture of both aprotinin and EACA as in groups II and III (10,000 KIU/kg aprotinin 100 mg/kg EACA after anesthetic induction, 10,000 KIU/kg aprotinin 100 mg/kg EACA in the CPB pump prime, and 10,000 KIU/kg aprotinin 100 mg/kg EACA over 3 hours after weaning from CPB). Anesthetic and surgical management were standardized in all patients, whose treatment differed only in the type of antifibrinolytic administered. All operations were performed by the same team, ruling out variation in surgical technique as a cause of varying postoperative blood loss. All patients were premedicated intramuscularly with 0.3 mg/kg morphine and 0.5 mg/kg phenergan 1 hour before operation. Anesthesia was induced intravenously with 1 mg/kg ketamine, 0.05 mg/kg midazolam, and 0.1 mg/kg pancuronium to facilitate tracheal intubation. Anesthesia was maintained with incremental fentanyl up to 10 g/kg, pancuronium, and isoflurane in air and oxygen (50%). Cardiopulmonary bypass was conducted at moderate hypothermia (28 C) using a membrane oxygenator (Minimax, Medtronic, Anaheim, CA). Systemic heparinization was with bovine intestinal mucosal heparin 400 IU/kg, keeping the kaolin activated clotting time (ACT) more than 600 seconds as per the center s protocol in the presence of antifibrinolytics. The CPB circuit was primed with 25 ml/kg Ringer s lactate solution, 0.5 g/kg (w/v) mannitol (20%), and 1 ml/kg (w/v) sodium bicarbonate (7.5%). Blood was added to the prime if needed to maintain a hematocrit of 25% on CPB. Pump flows were 150 ml/kg at normothermia and 100 ml/kg during hypothermia. Time taken for sternal closure after protamine was noted as an index of surgical hemostasis in all patients. Postoperative care was provided by a separate team of intensivists, blinded to the antifibrinolytic given, with full freedom for postoperative management as per existing protocols. Postoperatively, the cumulative hourly blood loss was noted at 24 hours from the time of admission to the intensive care unit. Use of blood and blood products was noted. Coagulation parameters were investigated at 6 hours including hematocrit, ACT, fibrinogen, partial thromboplastin time (PTT), thrombin time (TT), platelet count, and fibrin degradation products (FDP). The number of patients reexplored for increased mediastinal drainage was also recorded. Results expressed as mean standard deviation were analyzed by analysis of variance (ANOVA) between the groups followed by Student s and Neuman-Keuls multiple range tests. A value of p 0.05 was considered significant. Results This study was conducted on 300 patients with congenital cyanotic heart disease undergoing open cardiac repair. The four groups of patients were comparable in all respects. The age of patients ranged from 2.5 months to 14 years. Demographic data are shown in Table 1. Table 2 shows the various operative procedures performed. Operative procedures were similarly distributed in the four groups. Intraoperative data are shown in Table 3. Preoperative hematocrit and hematocrit values on CPB were similar in the four groups. Time taken for sternal closure was

3 1310 CHAUHAN ET AL Ann Thorac Surg APROTININ, EACA, AND MIXTURE COMPARED 2000;70: Table 2. Operative Procedures Operative Procedure TOF correction Modified Fontan Senning TAPVC repair TAPVC total anomalous pulmonary venous connection; tetralogy of Fallot. TOF longest in group I (68 12 min), significantly different compared with only (51 8 min), p Urine output on CPB was comparable in all four groups (not significant [NS]). Postoperative data are shown in Table 4. Cumulative blood loss at 24 hours (ml/kg) was greatest in group I (36 19) and least in (29 12); in group II it was and in group III it was ( p 0.01, group I versus ; p 0.05, group I versus groups II and III). Use of packed red blood cells (PRBC) reflected the blood loss and was maximum in group I (18 12 ml kg 1 24 h 1 ) and least in (11 9mL kg 1 24 h 1 ; in group II it was ml kg 1 24 h 1 and in group III it was 14 9mL kg 1 24 h 1 ( p 0.01, group I versus ; p 0.05, group I versus groups II and III). Fresh frozen plasma (FFP) used for volume replacement when hematocrit was less than 35% was similar in the four groups (NS). Platelet concentrate use was significantly greater in group I compared with groups II to IV ( p 0.01; see Table 4). Tests of coagulation done at 6 hours are shown in Table 5. Fibrinogen levels were lowest in the control group compared with groups II to IV ( p 0.01; see Table 5). ACT, PTT, and TT were similar in all four groups. Fibrinogen degradation products (split) were highest in group I compared with groups II to IV ( p 0.01). Reexploration for increased postoperative bleeding was highest in group I (11 of 80, 13%) and lowest in (1 of 60, 1.65%); in group II it was 6 of 100 (6%) and in group III it was 2 of 60 (3.3%). Comment Use of the CPB circuit during cardiac operations causes a severe disruption of the coagulation system by initiating fibrinolysis and causing platelet dysfunction. Children with congenital cyanotic heart disease have an already deranged coagulation system [12]. They are known to have increased fibrinolysis and altered platelet function. The use of antifibrinolytics to reduce CPB-induced postoperative blood loss is therefore a very attractive proposition in these children. Aprotinin, which is an antifibrinolytic agent and also protects platelets by preventing their activation on CPB, is ideal for this situation. Epsilon aminocaproic acid has the advantage over aprotinin of lower cost, lack of anaphylactic reactions, and suitability for use during subsequent surgical procedure as it is a synthetic agent in contrast to the bovine origin of aprotinin. Our study found EACA to be as effective as low dose aprotinin in reducing blood loss after primary open cardiac operation in cyanotic children. This could be of considerable significance if the relative cost of the two drugs is considered. Requirement of PRBCs and platelet concentrates was significantly reduced in the three study groups compared with the control group. This justifies the routine use of either of the two antifibrinolytics in cyanotic congenital heart disease. Gralnick [10] studied preoperative EACA in four patients, 2 of whom were children with cyanotic heart disease, and found an oral loading dose of 2 g followed by 200 to 500 mg/h infusion during the operation and 6 to 8 hours postoperatively, to reduce intraoperative and postoperative blood loss, which was 10 and 20 ml kg 1 24 h 1 in the 2 children compared with 35 ml kg 1 12 h 1 reported in 40 comparable patients operated for congenital cyanotic heart disease from 1962 to 1967 at the National Institutes of Health. McLure and Izsak [11] studied 71 children with congenital heart disease, 56 of whom completed the study. Of these 31 who received placebo infusion, 13 were acyanotic, and only 12 cyanotic patients received EACA infusion. The dose used was 75 mg/kg loading in the first hour and 15 mg kg 1 h 1 thereafter. The blood loss reduction was found to be 42% in the cyanotic group. The author recommended that EACA should be used rou- Table 3. Intraoperative Data a Intraoperative Data p CPB time (min) NS Sternal closure time (min) b Hematocrit (%), preoperative NS Hematocrit (%), on CPB NS Hematocrit (%), postoperative NS Temperature on CPB ( C) NS Urine on CPB (ml kg 1 h 1 ) NS b. CPB cardiopulmonary bypass; NS not significant.

4 Ann Thorac Surg CHAUHAN ET AL 2000;70: APROTININ, EACA, AND MIXTURE COMPARED 1311 Table 4. Postoperative Data a Postoperative Data p NS Blood loss PRBC FFP PC groups II, III groups II, III groups II, IV groups II IV Reexploration (%) 11/80 (13) 6/100 (6) 2/60 (3.3) 1/60 (1.65) groups III, IV versus versus group III; group II versus groups III, IV; group III versus... versus group II; group II versus FFP fresh frozen plasma; NS not significant; PC platelet concentrate; PRBC packed red blood cells. group III; group III versus tinely in patients with cyanotic congenital heart disease who are expected to be on bypass for more than 1 hour. We also found EACA to significantly reduce blood loss and blood and blood product usage compared with patients in the control group. Some studies have shown no benefit in using aprotinin to reduce postoperative blood loss [13, 14]. Davies and colleagues [13] studied 42 patients designed to receive placebo or aprotinin and found aprotinin to be of no benefit in routine cardiac operations. However, their aprotinin group was small (19 patients), and of these 19 patients only 15 had operations such as total correction of tetralogy of Fallot, Fontan repairs, and reoperations that would have required an antifibrinolytic. They did find significantly increased FDP levels in the control group, signifying increased fibrinolysis, and also a significantly reduced hemoglobin loss in the patients receiving aprotinin. Our study differs from that of Boldt and associates [14], who in a prospective randomized study found less than 35,000 KIU/kg aprotinin not to reduce postoperative blood loss. However, their patient group also was small. The combination of aprotinin and EACA used in this study was marginally better than either aprotinin or EACA alone in reducing postoperative blood loss and platelet concentrate requirement, but compared with patients not given any antifibrinolytic, combination therapy was the most effective and blood loss, PRBC, and platelet concentrate requirements were least in this group. This is probably due to the fact that whereas EACA acts by inhibiting plasminogen activator substances, and to a lesser degree by antiplasmin activation, aprotinin acts by inhibiting plasmin and kallikrein and other proteases. Their actions are therefore complementary. In conclusion, this study conducted on children with cyanotic heart disease undergoing corrective surgical procedures on bypass found 1. Both antifibrinolytics EACA and low dose aprotinin were effective in reducing postoperative blood loss and requirements of PRBC and platelet concentrate compared with the control group given no drug. 2. EACA was equally as effective as low dose aprotinin in reducing postoperative blood loss and transfusion requirements. 3. The combination of EACA and aprotinin was only slightly more effective than either of the two agents alone, although more significant statistically when compared with the control group. Table 5. Coagulation Tests at 6 Hours a Test p ACT (s) NS Fibrinogen b (mg/dl) PTT (s) NS TT (s) NS PC c ( 10 9 /L) FDP ( g/ml) b b groups II IV. c. ACT activated clotting time; FDP fibrin degradation products (split); NS not significant; PC platelet concentrate; PTT partial thromboplastin time; TT thrombin time.

5 1312 CHAUHAN ET AL Ann Thorac Surg APROTININ, EACA, AND MIXTURE COMPARED 2000;70: The authors thank Mr Rajesh Kumar Ahuja, MSc, for the statistical analysis. References 1. Hartstein G, Jarssens M. Treatment of excessive mediastinal bleeding after cardiopulmonary bypass. Ann Thorac Surg 1996;62: Kern FH, Morana MJ, Sears JL, Hickey PR. Coagulation defects in neonates undergoing cardiopulmonary bypass. Ann Thorac Surg 1992;54: Guay J, Rivard GJ. Mediastinal bleeding after cardiopulmonary bypass in pediatric patients. Ann Thorac Surg 1996;62: Hardy JF, Belisle S. Natural and synthetic antifibrinolytics in adult cardiac surgery: efficacy, effectiveness and efficiency. Can J Anesth 1994;41: Hunt BJ, Yacoub M. Aprotinin and cardiac surgery: reduces blood loss. Br Med J 1991;303: Herynkopf F, Lucchese F, Pereira E, Kalil R. Aprotinin in children undergoing correction of congenital heart defects: a double blind pilot study. J Thorac Cardiovasc Surg 1994;108: Tabuchi N, De-Haan J, Boonstra PW, Huet RCG. Aprotinin effect on platelet function and clotting during cardiopulmonary bypass. Eur J Cardiothorac Surg 1994;8: Vander Salm TJ, Ansell JE, Okike ON, et al. The role of epsilon aminocaproic acid in reducing bleeding after cardiac operation: a double blind randomised study. J Thorac Cardiovasc Surg 1998;95: Jordan D, Delphin E, Rose E. Prophylactic E aminocaproic acid (EACA) administration minimises blood replacement therapy during cardiac surgery. Anesth Analg 1995;80: Gralnick HR. -Aminocaproic acid in preoperative correction of haemostatic defect in cyanotic congenital heart disease. Lancet 1970;7658: Mc Lure PD, Izsak J. The use of epsilon aminocaproic acid to reduce bleeding during cardiac bypass in children with congenital heart disease. Anesthesiology 1974;40: Papov-Cenic S, Urban AE, Noe G. Studies on the cause of bleeding during and after surgery with a heart lung machine in children with cyanotic and acyanotic congenital cardiac defects and their prophylactic treatment. In: Papov-Cenic S, ed. Role of chemical mediators in pathophysiology of acute illness and injury. New York: Raven Press, 1982: Davies MJ, Alison A, Kort H, Weerasena NA, Rocco D. Prospective randomised double blind study of high dose aprotinin in pediatric cardiac operations. Ann Thorac Surg 1997;63: Boldt J, Knothe C, Zickmann B, Wege N, Dapper F. Comparison of two aprotinin dosage regimens in pediatric patients having cardiac operations. Influence on platelet function and blood loss. J Thorac Cardiovasc Surg 1993;105: Discussion Groups on the Internet The following three articles will be published in the November 2000 issue of The Annals of Thoracic Surgery, and have been selected for discussion topics on the Internet. These discussion groups can be accessed by going to the Society of Thoracic Surgeons Home Page ( and clicking on Discussion Forums. We encourage everyone to participate, as our goal is to make the discussion as interactive as possible. Lung Transplantation Is Warranted for Stable, Ventilator-Dependent Recipients Bryan F. Meyers, MD, John P. Lynch, MD, Richard J. Battafarano, MD, Tracey J. Guthrie, BSN, Elbert P. Trulock, MD, Joel D. Cooper, MD, and G. Alexander Patterson, MD Stage Biventricular Repair of Pulmonary Atresia or Stenosis With Intact Ventricular Septum Shunji Sano, MD, Kozo Ishino, MD, Masaki Kawada, MD, Emi Fujisawa, MD, Masahiro Kamada, MD, and Shin-ichi Ohtsuki, MD Off-Pump Versus On-Pump Coronary Bypass in High Risk Subgroups Taro Yokoyama, MD, PhD, Fritz J. Baumgartner, MD, Ali Gheissari, MD, Eli R. Capouya, MD, George P. Panagiotides, MD, and Richard J. Declusin, MD Tom R. Karl, MD Internet Annals Editor Philadelphia, Pennsylvania karl@ .chop.edu by the Society of Thoracic Surgeons Ann Thorac Surg 2000;70: /00/$20.00 Published by Elsevier Science Inc

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