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Evaluation of Epsilon Amino-Caproic Acid (EACA) and Autologous Blood as Blood Conservation Strategies in Patients Undergoing Cardiac Surgery
ORIGINAL ARTICLE
Original Article
Evaluation of Epsilon Amino-Caproic Acid (EACA) and Autologous Blood as Blood Conservation Strategies in Patients Undergoing Cardiac Surgery Vishal Sharma, MD ∗ , Sachin Talwar, MCh, Shiv Kumar Choudhary, MCh, Rama Lakshmy, MD, Shailaja Kale, MD and Arkalgud Sampath Kumar, MCh Cardiothoracic Centre, All India Institute of Medical Sciences, New Delhi, India
Background: To evaluate the effects of autologous blood and Epsilon amino-caproic acid on intra-operative and postoperative blood loss and homologous blood product requirements in patients undergoing cardiac surgery. Methods: Patients were randomly allocated to two groups of 30 each. In the Epsilon amino-caproic acid (EACA) group, the drug was administered in a loading dose of 100 mg/kg before skin incision followed by an infusion of 1/5th the loading dose hourly and terminated 3 h after heparin neutralization. In the autologous transfusion (AT) group, 10% of the calculated whole blood volume was collected intra-operatively before cardiopulmonary bypass and re-infused after its termination. Results: Haemoglobin values were comparable pre-operatively, on cardiopulmonary bypass, off cardiopulmonary bypass and post-operatively on day two in both groups. Intra-operative blood loss was not significantly different (643.3 ± 129.14 ml in group EACA versus 710 ± 145.5 ml in group AT, p = 0.66). Although the chest drainage was more in group AT during 0–3 h (71.3 ± 54.3 ml versus 112.6 ± 79.3.6 ml, p = 0.006) it was comparable amongst in the first 24 h (231.1 ± 98.3 ml in group AT versus 235 ± 101.4 ml in group EACA, p = 0.88). Homologous blood product requirements were similar in both groups. Conclusion: Autologous blood is as efficacious as Epsilon amino-caproic acid for blood conservation in cardiac surgery. (Heart, Lung and Circulation 2006;15:261–265) © 2006 Australasian Society of Cardiac and Thoracic Surgeons and the Cardiac Society of Australia and New Zealand. Published by Elsevier Inc. All rights reserved. Keywords. Blood conservation; Autologous blood; Epsilon amino-caproic acid
Introduction
B
lood loss and coagulopathy with consequent homologous blood transfusion are major problems in cardiac surgery and are related to haemostatic changes such as platelet dysfunction, inactivation of clotting factors and hyperfibrinolysis.1–3 Autologous blood (AB) products represent the safest source of transfusion and eliminate the disadvantages of homologous blood. The main advantage of using anti-fibrinolytics is that they are readily available, easy to administer, avoid the use of expensive equipment and may be used prophylactically rather than therapeutically. Although manipulation of haemostasis with anti-fibrinolytics carries the possible risk of an irreversible thrombotic tendency, such complications are rarely reported in cardiac patients.4–7 Despite the availability of enormous data, there is no consensus Received 22 March 2006; received in revised form 29 March 2006; accepted 31 March 2006; available online 12 May 2006 ∗
Corresponding author. Present address: 201-H MIG flats, Rajouri Garden, New Delhi 110027, India. Tel.: +91 11 41440522. E-mail address: [email protected] (V. Sharma).
regarding the most effective method of reducing postoperative blood loss. Thus, the present study was designed to evaluate Epsilon amino-caproic acid (EACA) and AB as blood conservation strategies in patients undergoing cardiac valve surgery under cardiopulmonary bypass (CPB).
Patients and Methods The study was conducted at All India Institute of Medical Sciences, New Delhi, India between January 2004 and December 2004 after obtaining ethics committee approval and informed consent from the patients. In order to have a similar patient profile in both the groups, 60 adult patients undergoing either valve repair/replacement under CPB were enrolled for the study. Exclusion criteria were as follows: history of bleeding or platelet disorder, prothrombin time (PT) >1.5 times the control values, bleeding time >8 min, congenital heart disease, blood urea >50 mg%, weight less than 45 kg or a pre-operative haemoglobin (Hb) less than 12 g/dl, re-do valve surgery, unstable angina or recent myocardial infarction and critical aortic stenosis.
© 2006 Australasian Society of Cardiac and Thoracic Surgeons and the Cardiac Society of Australia and New Zealand. Published by Elsevier Inc. All rights reserved.
1443-9506/04/$30.00 doi:10.1016/j.hlc.2006.03.014
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Heart, Lung and Circulation 2006;15:261–265
Patients on anticoagulant therapy with warfarin were switched over to plain heparin 48 h before surgery. Heparin was discontinued 6 h prior to the surgical procedure. Those who had received thrombolytic therapy less than 6 weeks prior to surgery and anti-platelet drugs within 1 week of surgery were excluded from the study. Subjects were randomly allocated (by a computer generated random number sequence) to one of the two groups of 30 each to complete the study in a given time frame. In group EACA, EACA was administered in a loading dose of 100 mg/kg before skin incision followed by a constant infusion at 1/5th the loading dose per hour and terminated 3 h after heparin neutralization with protamine. In group AT (autologous transfusion), intra-operative AB was collected (approximately 10% of the calculated whole blood volume) before CPB and within 10 min after central venous cannulation by gravity drainage through an internal jugular 8 F catheter into blood collection bags containing citrate–phosphate–dextrose anti-coagulant, thus ensuring low shear effects on the platelets. Blood volume was maintained with a simultaneous infusion of an equivalent amount of 6% Haes-steril, Pentastarch (Fresenius Kabi, India Pvt. Ltd.). The whole blood units were kept at room temperature in the operating room and re-infused after discontinuation of CPB and protamine administration. The maximum volume of blood donated (Vbl) to maintain the hemoglobin above a predetermined minimal level (Hb e min) was calculated by the following formula:
Vbl = Vb − (Vb + Vc)
Hb e min Hbi
where Vb = estimated blood volume of the patient; Vc = extracorporeal circuit prime; Hbi = initial hemoglobin. All patients received a Thiopentone-opiod based anaesthetic technique supplemented with benzodiazepines, muscle relaxants and inhalational anaesthetic agents. Heparin in a dose of 300 U/kg was used 3 min before aortic cannulation. The activated coagulation time (ACT, kaolin) was used to monitor the coagulation status. An ACT of >480 s was taken as satisfactory anticoagulation. Hypothermic CPB (32 ◦ C) was conducted using a membrane oxygenator and Ringers lactate solution pump prime in all patients. Cold cardioplegia solution containing potassium was used to induce and maintain cardiac arrest during aortic cross clamping. Myocardial preser-
vation was achieved with systemic cooling to 32 ◦ C and use of topical ice-slush. On CPB, a dilutional hematocrit of 21% was maintained. After termination of CPB, protamine was administered in the ratio of 1.3 mg to 100 U of the initial dose of heparin. Additional doses of protamine were administered if ACT did not return to normal value or within 10% of baseline value. Criteria for transfusion of blood products were: 1. Packed Red Blood Cells (PRBC’s) were given for – (a) Hb <7 g% on CPB (b) Hb <9 g% after discontinuation of CPB (c) Chest tube drainage • >10 ml/kg for first hour • >20 ml/kg for first 3 h • >300 ml/h in any 1 h 2. Fresh frozen plasma (FFP) was given for active bleeding or factor deficiency 3. Platelet transfusion was given for counts <100,000/mm3 The demographic, laboratory and surgical predictor variables studied were: age, sex, height, weight, preoperative Hb and Hb during, post-CPB and at 2nd postoperative day, pre-operative and post-operative platelet count (at 2nd post-operative day), pre-operative and postoperative PT (at 2nd post-operative day), pre-operative and post-operative bleeding time (at 2nd post-operative day), pre-heparin and post-protamine ACT, pre-operative and post-operative blood urea, pre-operative and postoperative liver function tests (LFT), CPB time (min), aortic cross-clamp time (min), surgical procedure performed and duration of surgery. The surgical outcome was determined by evaluation of total blood loss in the operating room (OR) as assessed by weighing of swabs and measurement of collection in the suction bottle; hourly chest tube drainage (CTD) in the intensive care unit (ICU) during first 6 h, then at 48 h up to the removal of chest tubes; requirement of blood and blood products in the OR, ICU and ward till the time of discharge from the hospital; re-exploration for bleeding and any mortality.
Statistical Analysis All values are expressed as median and mean ± standard deviation. Group comparison for continuous variables was performed by Student’s t-test and categorical variables by
Table 1. Baseline Characteristics Demographic and Operative Detail of Patients Group EACA (Mean ± S.D.) ± ± ± ± ±
Age (years) Weight (kg) Height (cms) CPB time (min) Aortic cross-clamp time (min)
32.8 52.16 154.2 62.5 43.3
ACT (s) Pre-heparin Post-protamine INR
126.8 ± 15.45 120.5 ± 20.09 2.16 ± 0.613
Group AT (Mean ± S.D.)
p-Value
± ± ± ± ±
12.37 9.97 5.65 17.78 16.02
0.43 0.96 0.86 0.98 0.78
128.4 ± 19.3 123.6 ± 12.86 2.16 ± 0.720
0.71 0.48 0.97
11.59 6.95 6.25 16.79 13.36
CPB: cardiopulmonary bypass; ACT: activated coagulation time; INR: international normalized ratio.
35.2 52.2 153.4 62.4 44.3
Sharma et al. Blood conservation in cardiac surgery
Table 2. Laboratory and Surgical Variables – Haemoglobin Group EACA Pre-operatively ON CPB OFF CPB Post-operatively (day 2)
12.5 7.9 10 11.6
± ± ± ±
0.4 1.6 1.12 0.95
Group AT
p-Value
± ± ± ±
0.39 0.61 0.41 0.13
12.6 7.7 9.8 11.03
0.5 1.4 1.13 1.8
CPB: cardiopulmonary bypass.
chi-square test; p < 0.05 was deemed statistically significant.
Results The two groups were comparable for age, weight, sex, height, CPB time, aortic cross-clamp time, ACT and INR values. The ACT before heparin and after protamine did not differ significantly in both the groups (Table 1). Haemoglobin values were comparable for both the groups pre-operatively, on CPB, Off CPB and postoperatively on day 2 (Table 2). Although the median intraoperative blood loss was more in group AT as compared to the group EACA (643 ± 129.4 ml versus 710 ± 145.5 ml, p = 0.66), the result was statistically not significant. The volume of blood collected in the chest drains in the ICU was significantly more in the AT group as compared to the EACA group for the first 3 h (36.2 ± 28.97 ml versus 19.6 ± 18.09 ml at first hour, p = 0.022; 73 ± 51.67 ml versus 45.3 ± 32.34 ml at second hour, p = 0.018; 112.6 ± 79.26 ml versus 71.3 ± 54.31 ml at 3 h, p = 0.006) (Table 3). Thereafter, till 48 h the chest drainage was comparable in both the groups. Blood/Blood product requirement was similar in both the groups in the OR and the ICU is detailed in Table 4 and was similar in both groups.
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No patient had any re-exploration for bleeding and there were no hospital deaths.
Discussion This study of the evaluation of EACA and AB for blood conservation in patients undergoing cardiac valve surgery under CPB demonstrates that both these strategies are equally efficacious in terms of intra-operative, postoperative blood loss and homologous blood product requirements. This could be related to the difference in the trends of intra-operative and post-operative blood loss in both the groups. Whereas patients in the EACA group bled more in the post-operative period after its infusion was terminated, those in the AB group bled more in the intra-operative period and early post-operative period. Thus the total blood loss and requirement of homologous blood products was comparable between both the groups. The patients in the present series had a pre-operative mean Hb of 13.35 ± 1.19 g% (range 12–17 g%) and a mean weight of 52.2 ± 6.2 kg (range 46–80 kg), so that we could safely withdraw approximately 10% of blood volume. Kaplan et al.8 reported that as much as 15% of the blood volume could be removed in patients with a normal hematocrit. Tempe et al.9 were able to remove only approximately 7% of blood volume in patients with a hematocrit less than 35% and 10% when more than 35%. We observed that chest drainage was significantly less in EACA group during the first 3 h. Thereafter, it was comparable with autologous blood group till 48 h postoperatively, thus, highlighting the difference in trends of bleeding amongst both the groups. This may be because EACA was discontinued 3 h after protamine administration and its effect would have worn off by 3 h (EACA has a
Table 3. Comparison of Chest Tube Drainage amongst the Two Groups Chest Tube Drainage (ml) First 4 h 4–24 h 24–48 h
Group EACA (Mean ± S.D.) (Median) 123.3 ± 64.4 (102) 231.1 ± 98.3 (180) 268.4 ± 104.9 (220)
Group AT (Mean ± S.D.) (Median)
p-Value
127 ± 74.6 (135) 235 ± 101.4 (220) 275.3 ± 16.2(320)
0.84 0.88 0.84
EACA: Epsilon amino-caproic acid; S.D.: standard deviation.
Table 4. Distribution of Blood and Blood Product Requirement Group EACA (Mean ± S.D.)
Group AT (Mean ± S.D.)
p-Value
132.4 ± 60.3 196.9 ± 42
140.2 ± 66.1 243.1 ± 44.3
0.76 0.06
Fresh frozen plasma (ml) Platelet concentrate (ml) Total (ml)
85 ± 38.4 12 ± 16.4 430.3 ± 157.2
91.37 ± 42.6 12.6 ± 16.9 452.6 ± 168.5
0.55 0.89 0.61
ICU PRBC (ml) Fresh frozen plasma (ml) Platelet concentrate (ml)
365 ± 111.2 134.6 ± 60.2 25 ± 32.4
375 ± 124.3 141 ± 68.1 30 ± 41.2
0.76 0.76 0.69
515 ± 151.2
527 ± 162.4
0.84
OR PRBC (ml) On CPB Post CPB
Total (ml)
EACA: Epsilon amino-caproic acid; ICU: intensive care unit OR: operating room, PRBC: packed red blood cells S.D.: standard deviation.
ORIGINAL ARTICLE
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Sharma et al. Blood conservation in cardiac surgery
half life of approximately 80 min). As intra-operative autologous blood withdrawal is known to protect the pooled blood from the deleterious effects of CPB, following reinfusion after CPB, it may have contributed to less coagulation abnormalities, reduced post-operative bleeding and the need for allogenic blood products. There were only two patients (6.6%) in both the groups who did not require PRBC’s addition on CPB (and thereafter till the time of discharge). When the study was begun, we did not know whether intra-operative fresh AB or EACA would be efficient in reducing the homologous blood products requirements. For the purpose of safety of the patients, we had decided beforehand those with Hb less than 7 g% on CPB and less than 9 g% after termination of CPB would receive PRBC’s. Since complete avoidance of homologous blood products was not the aim of our study, we decided to continue our study despite the high risk of early re-transfusion. Patients in both the groups required PRBC’s upon termination of CPB also in order to maintain hemoglobin of 9 g%. Diprose et al.10 have reported that in addition to intra-operative cell salvage, aprotinin is the most efficacious pharmacological therapy for reducing patients’ exposure to allogenic blood transfusion during first time cardiac surgery. Since we wanted to define the contribution offered by each method, we did not combine any other intra-operative blood conservation strategy or salvage the blood left in the oxygenator for both volume expansion and to raise the patients’ hematocrit. Although patients did not bleed excessively in the ICU, PRBC’s were transfused to maintain hemoglobin values above 9 g%. Use of fresh frozen plasma and platelet concentrates were also comparable in both the groups. We observed that EACA did not significantly decrease homologous blood products requirements as compared to autologous blood withdrawal. This lack of efficacy may be related to patient-to-patient dose response variation, unidentified surgical risk factors and should be further evaluated. The observations of the present study are in agreement with others11 who concluded that despite the efficacy of EACA in reducing post-operative blood loss, homologous blood products requirements were not significantly different in those patients where auto transfusions were used. Thus, our study highlights that both these strategies for blood conservation in cardiac surgery are comparable and follow different trends in terms of reduction of intra-operative, post-operative blood loss and homologous blood products requirements. In a meta-analysis of the various pharmacological studies to decrease excessive blood loss, it was concluded that the use of aprotinin and lysine analogues did reduce the amount of bleeding12 ; however, our experience with EACA is contrary to this study.
Study Limitations This study might be criticized because of the absence of a placebo control group. However, in view of previous studies describing blood transfusion requirements in patients in whom no blood conservation strategies were
Heart, Lung and Circulation 2006;15:261–265
used, randomizing patients into a treatment group that would probably be exposed to greater allogenic blood requirements (and blood-induced complications) was ethically unacceptable.13,14 Also, autologous blood withdrawal could only be used in patients with high pre-operative haemoglobin values as the intra-operative blood collection before CPB further lowers the patients haemoglobin concentration. This increases the need for transfusion of PRBC’s during CPB for anemia. Patients with high haemoglobin values before cardiac surgery are relatively rare. Another limitation of our study is that we excluded patients with known coagulopathies and on pre-operative anti-coagulant treatment. This limits the broad application of our study. However, with repeated measurements of the blood loss in 30 patients in each group, the power of the study was estimated to be 99.5% (α value 5%), which indicates that a similar blood loss (p = 0.84) up to 48 h was not merely co-incidental and that the post-operative blood loss was indeed similar in both groups.
Conclusions As the intra-operative, post-operative blood loss and homologous blood product requirements were comparable in both the groups, we conclude that withdrawal of autologous blood prior to heparinization followed by reinfusion is as efficacious as epsilon amino-caproic acid for blood conservation in cardiac valve surgery patients.
References 1. Havel M, Teufelsbauer H, Knobl P. The effect of intraoperative aprotinin administration on post-operative bleeding in patients undergoing cardiopulmonary bypass surgery. J Thorac Cardiovasc Surg 1991;101:968–72. 2. Knobl PN, Zilla P, Fasol R. The protein C system in patients undergoing cardiopulmonary bypass. J Thorac Cardiovasc Surg 1987;94:600–5. 3. Hiratzka LH, Richardson JV, Brandt B. The effect of autologous blood salvage techniques upon bank blood usage and cost of routine coronary revascularization. Perfusion 1986;1:239–44. 4. Hoffman EP, Koo AH. Cerebral thrombosis associated with Amicar. Radiology 1979;131:687–9. 5. Naeye L. Thrombotic state after hemorrhagic diathesis, a possible complication of therapy with E-aminocaproic acid. Blood 1962;19:694–701. 6. Rydin E, Lundberg PO. Tranexamic acid and intracranial thrombosis. Lancet 1976;2:49–51. 7. Sonntang VKH, Stein BM. Arteriopathic complications during treatment of sub-arachnoid haemorrhage with Eaminocaproic acid. J Neurosurg 1974;40:480–5. 8. Kaplan JA, Cannarella C, Jones EL. Autologous blood transfusion during cardiac surgery. A re-evaluation of three methods. J Thorac Cardiovasc Surg 1977;74:4–10. 9. Tempe D, Bajwa R, Cooper A, Nag B, Tomar AS, Khanna SK, et al. Blood conservation in small adults undergoing valve surgery. J Cardiothorac Vasc Anesth 1996;10:502–6. 10. Diprose P, Herberston MJ, O’Shaughnessy D, Deakin CD, Gill RS. Reducing allogenic transfusion in cardiac surgery:a randomized double-blind placebo-controlled trial of antifibrinolytic therapies used in addition to intra-operative cell salvage. Br J Anaesth 2005;94:271–8.
11. Penta de Peppo A, Pierri MD, Scafuri A, De Paulis R, Coluntuono G, Capara E, et al. Intra-operative antifibrinolysis and blood-saving techniques in cardiac surgery. Prospective trial of 3 antifibrinolytic drugs. Tex Heart Inst J 1995;22:231–6. 12. Levi M, Cromheecke ME, de Jonge E, Prins MH, de Mol BJ, Briet E, et al. Pharmacological strategies to decrease exsceesive blood loss in cardiac surgery: a meta-analysis of clinically relevant end points. Lancet 1999;354:1940–7.
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13. Liu YC, Tsai TP. The effect of coagulation protection with combination of epsilon amino-caproic acid and plasma saver in open-heart surgery. Acta Anaesthesiol Scan 1998;36:149– 54. 14. Kochamba GS, Pfeffer TA, Sintek CF, Khonsari S. Intraoperative autotransfusion reduces blood loss after cardiopulmonary bypass. Ann Thorac Surg 1996;61:900–3.
ORIGINAL ARTICLE
Heart, Lung and Circulation 2006;15:261–265
Original Article
Evaluation of Epsilon Amino-Caproic Acid (EACA) and Autologous Blood as Blood Conservation Strategies in Patients Undergoing Cardiac Surgery Vishal Sharma, MD ∗ , Sachin Talwar, MCh, Shiv Kumar Choudhary, MCh, Rama Lakshmy, MD, Shailaja Kale, MD and Arkalgud Sampath Kumar, MCh Cardiothoracic Centre, All India Institute of Medical Sciences, New Delhi, India
Background: To evaluate the effects of autologous blood and Epsilon amino-caproic acid on intra-operative and postoperative blood loss and homologous blood product requirements in patients undergoing cardiac surgery. Methods: Patients were randomly allocated to two groups of 30 each. In the Epsilon amino-caproic acid (EACA) group, the drug was administered in a loading dose of 100 mg/kg before skin incision followed by an infusion of 1/5th the loading dose hourly and terminated 3 h after heparin neutralization. In the autologous transfusion (AT) group, 10% of the calculated whole blood volume was collected intra-operatively before cardiopulmonary bypass and re-infused after its termination. Results: Haemoglobin values were comparable pre-operatively, on cardiopulmonary bypass, off cardiopulmonary bypass and post-operatively on day two in both groups. Intra-operative blood loss was not significantly different (643.3 ± 129.14 ml in group EACA versus 710 ± 145.5 ml in group AT, p = 0.66). Although the chest drainage was more in group AT during 0–3 h (71.3 ± 54.3 ml versus 112.6 ± 79.3.6 ml, p = 0.006) it was comparable amongst in the first 24 h (231.1 ± 98.3 ml in group AT versus 235 ± 101.4 ml in group EACA, p = 0.88). Homologous blood product requirements were similar in both groups. Conclusion: Autologous blood is as efficacious as Epsilon amino-caproic acid for blood conservation in cardiac surgery. (Heart, Lung and Circulation 2006;15:261–265) © 2006 Australasian Society of Cardiac and Thoracic Surgeons and the Cardiac Society of Australia and New Zealand. Published by Elsevier Inc. All rights reserved. Keywords. Blood conservation; Autologous blood; Epsilon amino-caproic acid
Introduction
B
lood loss and coagulopathy with consequent homologous blood transfusion are major problems in cardiac surgery and are related to haemostatic changes such as platelet dysfunction, inactivation of clotting factors and hyperfibrinolysis.1–3 Autologous blood (AB) products represent the safest source of transfusion and eliminate the disadvantages of homologous blood. The main advantage of using anti-fibrinolytics is that they are readily available, easy to administer, avoid the use of expensive equipment and may be used prophylactically rather than therapeutically. Although manipulation of haemostasis with anti-fibrinolytics carries the possible risk of an irreversible thrombotic tendency, such complications are rarely reported in cardiac patients.4–7 Despite the availability of enormous data, there is no consensus Received 22 March 2006; received in revised form 29 March 2006; accepted 31 March 2006; available online 12 May 2006 ∗
Corresponding author. Present address: 201-H MIG flats, Rajouri Garden, New Delhi 110027, India. Tel.: +91 11 41440522. E-mail address: [email protected] (V. Sharma).
regarding the most effective method of reducing postoperative blood loss. Thus, the present study was designed to evaluate Epsilon amino-caproic acid (EACA) and AB as blood conservation strategies in patients undergoing cardiac valve surgery under cardiopulmonary bypass (CPB).
Patients and Methods The study was conducted at All India Institute of Medical Sciences, New Delhi, India between January 2004 and December 2004 after obtaining ethics committee approval and informed consent from the patients. In order to have a similar patient profile in both the groups, 60 adult patients undergoing either valve repair/replacement under CPB were enrolled for the study. Exclusion criteria were as follows: history of bleeding or platelet disorder, prothrombin time (PT) >1.5 times the control values, bleeding time >8 min, congenital heart disease, blood urea >50 mg%, weight less than 45 kg or a pre-operative haemoglobin (Hb) less than 12 g/dl, re-do valve surgery, unstable angina or recent myocardial infarction and critical aortic stenosis.
© 2006 Australasian Society of Cardiac and Thoracic Surgeons and the Cardiac Society of Australia and New Zealand. Published by Elsevier Inc. All rights reserved.
1443-9506/04/$30.00 doi:10.1016/j.hlc.2006.03.014
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Heart, Lung and Circulation 2006;15:261–265
Patients on anticoagulant therapy with warfarin were switched over to plain heparin 48 h before surgery. Heparin was discontinued 6 h prior to the surgical procedure. Those who had received thrombolytic therapy less than 6 weeks prior to surgery and anti-platelet drugs within 1 week of surgery were excluded from the study. Subjects were randomly allocated (by a computer generated random number sequence) to one of the two groups of 30 each to complete the study in a given time frame. In group EACA, EACA was administered in a loading dose of 100 mg/kg before skin incision followed by a constant infusion at 1/5th the loading dose per hour and terminated 3 h after heparin neutralization with protamine. In group AT (autologous transfusion), intra-operative AB was collected (approximately 10% of the calculated whole blood volume) before CPB and within 10 min after central venous cannulation by gravity drainage through an internal jugular 8 F catheter into blood collection bags containing citrate–phosphate–dextrose anti-coagulant, thus ensuring low shear effects on the platelets. Blood volume was maintained with a simultaneous infusion of an equivalent amount of 6% Haes-steril, Pentastarch (Fresenius Kabi, India Pvt. Ltd.). The whole blood units were kept at room temperature in the operating room and re-infused after discontinuation of CPB and protamine administration. The maximum volume of blood donated (Vbl) to maintain the hemoglobin above a predetermined minimal level (Hb e min) was calculated by the following formula:
Vbl = Vb − (Vb + Vc)
Hb e min Hbi
where Vb = estimated blood volume of the patient; Vc = extracorporeal circuit prime; Hbi = initial hemoglobin. All patients received a Thiopentone-opiod based anaesthetic technique supplemented with benzodiazepines, muscle relaxants and inhalational anaesthetic agents. Heparin in a dose of 300 U/kg was used 3 min before aortic cannulation. The activated coagulation time (ACT, kaolin) was used to monitor the coagulation status. An ACT of >480 s was taken as satisfactory anticoagulation. Hypothermic CPB (32 ◦ C) was conducted using a membrane oxygenator and Ringers lactate solution pump prime in all patients. Cold cardioplegia solution containing potassium was used to induce and maintain cardiac arrest during aortic cross clamping. Myocardial preser-
vation was achieved with systemic cooling to 32 ◦ C and use of topical ice-slush. On CPB, a dilutional hematocrit of 21% was maintained. After termination of CPB, protamine was administered in the ratio of 1.3 mg to 100 U of the initial dose of heparin. Additional doses of protamine were administered if ACT did not return to normal value or within 10% of baseline value. Criteria for transfusion of blood products were: 1. Packed Red Blood Cells (PRBC’s) were given for – (a) Hb <7 g% on CPB (b) Hb <9 g% after discontinuation of CPB (c) Chest tube drainage • >10 ml/kg for first hour • >20 ml/kg for first 3 h • >300 ml/h in any 1 h 2. Fresh frozen plasma (FFP) was given for active bleeding or factor deficiency 3. Platelet transfusion was given for counts <100,000/mm3 The demographic, laboratory and surgical predictor variables studied were: age, sex, height, weight, preoperative Hb and Hb during, post-CPB and at 2nd postoperative day, pre-operative and post-operative platelet count (at 2nd post-operative day), pre-operative and postoperative PT (at 2nd post-operative day), pre-operative and post-operative bleeding time (at 2nd post-operative day), pre-heparin and post-protamine ACT, pre-operative and post-operative blood urea, pre-operative and postoperative liver function tests (LFT), CPB time (min), aortic cross-clamp time (min), surgical procedure performed and duration of surgery. The surgical outcome was determined by evaluation of total blood loss in the operating room (OR) as assessed by weighing of swabs and measurement of collection in the suction bottle; hourly chest tube drainage (CTD) in the intensive care unit (ICU) during first 6 h, then at 48 h up to the removal of chest tubes; requirement of blood and blood products in the OR, ICU and ward till the time of discharge from the hospital; re-exploration for bleeding and any mortality.
Statistical Analysis All values are expressed as median and mean ± standard deviation. Group comparison for continuous variables was performed by Student’s t-test and categorical variables by
Table 1. Baseline Characteristics Demographic and Operative Detail of Patients Group EACA (Mean ± S.D.) ± ± ± ± ±
Age (years) Weight (kg) Height (cms) CPB time (min) Aortic cross-clamp time (min)
32.8 52.16 154.2 62.5 43.3
ACT (s) Pre-heparin Post-protamine INR
126.8 ± 15.45 120.5 ± 20.09 2.16 ± 0.613
Group AT (Mean ± S.D.)
p-Value
± ± ± ± ±
12.37 9.97 5.65 17.78 16.02
0.43 0.96 0.86 0.98 0.78
128.4 ± 19.3 123.6 ± 12.86 2.16 ± 0.720
0.71 0.48 0.97
11.59 6.95 6.25 16.79 13.36
CPB: cardiopulmonary bypass; ACT: activated coagulation time; INR: international normalized ratio.
35.2 52.2 153.4 62.4 44.3
Sharma et al. Blood conservation in cardiac surgery
Table 2. Laboratory and Surgical Variables – Haemoglobin Group EACA Pre-operatively ON CPB OFF CPB Post-operatively (day 2)
12.5 7.9 10 11.6
± ± ± ±
0.4 1.6 1.12 0.95
Group AT
p-Value
± ± ± ±
0.39 0.61 0.41 0.13
12.6 7.7 9.8 11.03
0.5 1.4 1.13 1.8
CPB: cardiopulmonary bypass.
chi-square test; p < 0.05 was deemed statistically significant.
Results The two groups were comparable for age, weight, sex, height, CPB time, aortic cross-clamp time, ACT and INR values. The ACT before heparin and after protamine did not differ significantly in both the groups (Table 1). Haemoglobin values were comparable for both the groups pre-operatively, on CPB, Off CPB and postoperatively on day 2 (Table 2). Although the median intraoperative blood loss was more in group AT as compared to the group EACA (643 ± 129.4 ml versus 710 ± 145.5 ml, p = 0.66), the result was statistically not significant. The volume of blood collected in the chest drains in the ICU was significantly more in the AT group as compared to the EACA group for the first 3 h (36.2 ± 28.97 ml versus 19.6 ± 18.09 ml at first hour, p = 0.022; 73 ± 51.67 ml versus 45.3 ± 32.34 ml at second hour, p = 0.018; 112.6 ± 79.26 ml versus 71.3 ± 54.31 ml at 3 h, p = 0.006) (Table 3). Thereafter, till 48 h the chest drainage was comparable in both the groups. Blood/Blood product requirement was similar in both the groups in the OR and the ICU is detailed in Table 4 and was similar in both groups.
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No patient had any re-exploration for bleeding and there were no hospital deaths.
Discussion This study of the evaluation of EACA and AB for blood conservation in patients undergoing cardiac valve surgery under CPB demonstrates that both these strategies are equally efficacious in terms of intra-operative, postoperative blood loss and homologous blood product requirements. This could be related to the difference in the trends of intra-operative and post-operative blood loss in both the groups. Whereas patients in the EACA group bled more in the post-operative period after its infusion was terminated, those in the AB group bled more in the intra-operative period and early post-operative period. Thus the total blood loss and requirement of homologous blood products was comparable between both the groups. The patients in the present series had a pre-operative mean Hb of 13.35 ± 1.19 g% (range 12–17 g%) and a mean weight of 52.2 ± 6.2 kg (range 46–80 kg), so that we could safely withdraw approximately 10% of blood volume. Kaplan et al.8 reported that as much as 15% of the blood volume could be removed in patients with a normal hematocrit. Tempe et al.9 were able to remove only approximately 7% of blood volume in patients with a hematocrit less than 35% and 10% when more than 35%. We observed that chest drainage was significantly less in EACA group during the first 3 h. Thereafter, it was comparable with autologous blood group till 48 h postoperatively, thus, highlighting the difference in trends of bleeding amongst both the groups. This may be because EACA was discontinued 3 h after protamine administration and its effect would have worn off by 3 h (EACA has a
Table 3. Comparison of Chest Tube Drainage amongst the Two Groups Chest Tube Drainage (ml) First 4 h 4–24 h 24–48 h
Group EACA (Mean ± S.D.) (Median) 123.3 ± 64.4 (102) 231.1 ± 98.3 (180) 268.4 ± 104.9 (220)
Group AT (Mean ± S.D.) (Median)
p-Value
127 ± 74.6 (135) 235 ± 101.4 (220) 275.3 ± 16.2(320)
0.84 0.88 0.84
EACA: Epsilon amino-caproic acid; S.D.: standard deviation.
Table 4. Distribution of Blood and Blood Product Requirement Group EACA (Mean ± S.D.)
Group AT (Mean ± S.D.)
p-Value
132.4 ± 60.3 196.9 ± 42
140.2 ± 66.1 243.1 ± 44.3
0.76 0.06
Fresh frozen plasma (ml) Platelet concentrate (ml) Total (ml)
85 ± 38.4 12 ± 16.4 430.3 ± 157.2
91.37 ± 42.6 12.6 ± 16.9 452.6 ± 168.5
0.55 0.89 0.61
ICU PRBC (ml) Fresh frozen plasma (ml) Platelet concentrate (ml)
365 ± 111.2 134.6 ± 60.2 25 ± 32.4
375 ± 124.3 141 ± 68.1 30 ± 41.2
0.76 0.76 0.69
515 ± 151.2
527 ± 162.4
0.84
OR PRBC (ml) On CPB Post CPB
Total (ml)
EACA: Epsilon amino-caproic acid; ICU: intensive care unit OR: operating room, PRBC: packed red blood cells S.D.: standard deviation.
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half life of approximately 80 min). As intra-operative autologous blood withdrawal is known to protect the pooled blood from the deleterious effects of CPB, following reinfusion after CPB, it may have contributed to less coagulation abnormalities, reduced post-operative bleeding and the need for allogenic blood products. There were only two patients (6.6%) in both the groups who did not require PRBC’s addition on CPB (and thereafter till the time of discharge). When the study was begun, we did not know whether intra-operative fresh AB or EACA would be efficient in reducing the homologous blood products requirements. For the purpose of safety of the patients, we had decided beforehand those with Hb less than 7 g% on CPB and less than 9 g% after termination of CPB would receive PRBC’s. Since complete avoidance of homologous blood products was not the aim of our study, we decided to continue our study despite the high risk of early re-transfusion. Patients in both the groups required PRBC’s upon termination of CPB also in order to maintain hemoglobin of 9 g%. Diprose et al.10 have reported that in addition to intra-operative cell salvage, aprotinin is the most efficacious pharmacological therapy for reducing patients’ exposure to allogenic blood transfusion during first time cardiac surgery. Since we wanted to define the contribution offered by each method, we did not combine any other intra-operative blood conservation strategy or salvage the blood left in the oxygenator for both volume expansion and to raise the patients’ hematocrit. Although patients did not bleed excessively in the ICU, PRBC’s were transfused to maintain hemoglobin values above 9 g%. Use of fresh frozen plasma and platelet concentrates were also comparable in both the groups. We observed that EACA did not significantly decrease homologous blood products requirements as compared to autologous blood withdrawal. This lack of efficacy may be related to patient-to-patient dose response variation, unidentified surgical risk factors and should be further evaluated. The observations of the present study are in agreement with others11 who concluded that despite the efficacy of EACA in reducing post-operative blood loss, homologous blood products requirements were not significantly different in those patients where auto transfusions were used. Thus, our study highlights that both these strategies for blood conservation in cardiac surgery are comparable and follow different trends in terms of reduction of intra-operative, post-operative blood loss and homologous blood products requirements. In a meta-analysis of the various pharmacological studies to decrease excessive blood loss, it was concluded that the use of aprotinin and lysine analogues did reduce the amount of bleeding12 ; however, our experience with EACA is contrary to this study.
Study Limitations This study might be criticized because of the absence of a placebo control group. However, in view of previous studies describing blood transfusion requirements in patients in whom no blood conservation strategies were
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used, randomizing patients into a treatment group that would probably be exposed to greater allogenic blood requirements (and blood-induced complications) was ethically unacceptable.13,14 Also, autologous blood withdrawal could only be used in patients with high pre-operative haemoglobin values as the intra-operative blood collection before CPB further lowers the patients haemoglobin concentration. This increases the need for transfusion of PRBC’s during CPB for anemia. Patients with high haemoglobin values before cardiac surgery are relatively rare. Another limitation of our study is that we excluded patients with known coagulopathies and on pre-operative anti-coagulant treatment. This limits the broad application of our study. However, with repeated measurements of the blood loss in 30 patients in each group, the power of the study was estimated to be 99.5% (α value 5%), which indicates that a similar blood loss (p = 0.84) up to 48 h was not merely co-incidental and that the post-operative blood loss was indeed similar in both groups.
Conclusions As the intra-operative, post-operative blood loss and homologous blood product requirements were comparable in both the groups, we conclude that withdrawal of autologous blood prior to heparinization followed by reinfusion is as efficacious as epsilon amino-caproic acid for blood conservation in cardiac valve surgery patients.
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