Replacement of aprotinin by 1-aminocaproic acid in infants undergoing cardiac surgery: consequences for blood loss and outcome

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1 British Journal of Anaesthesia 110 (4): (2013) Advance Access publication 4 December doi: /bja/aes430 Replacement of aprotinin by 1-aminocaproic acid in infants undergoing cardiac surgery: consequences for blood loss and outcome K. Martin 1 *, R. Gertler 1, M. MacGuill 1, N. P. Mayr 1, A. Hapfelmeier 4,J.Hörer 2, M. Vogt 3, P. Tassani 1 and G. Wiesner 1 1 Department of Anaesthesiology, 2 Department of Cardiovascular Surgery, and 3 Department of Paediatric Cardiology and Congenital Heart Defects, Deutsches Herzzentrum München, Klinik an der Technischen Universität München, Munich, Germany 4 Institute of Medical Statistics and Epidemiology, Technische Universität München, Munich, Germany * Corresponding author. martin@dhm.mhn.de Editor s key points Paediatric patients are at high risk for haemostatic disorders after cardiopulmonary bypass. Antifibrinolytic agents are recommended by guidelines to reduce perioperative blood loss. The effects of the transition from the use of aprotinin to 1-aminocaproic acid on chest tube output (CTO) and outcome measures were assessed retrospectively at a single centre. CTO was lower with aprotinin, but there were no differences in transfusions or outcome. Background. Once aprotinin was no longer available for clinical use, 1-aminocaproic acid (EACA) and tranexamic acid became the only two options for antifibrinolytic therapy. We compared aprotinin and EACA with respect to their blood-sparing efficacy and other major clinical outcome criteria in infants undergoing cardiac surgery. Methods. We retrospectively analysed data from a large consecutive cohort of infants (n¼227) aged days undergoing primary cardiac surgery requiring cardiopulmonary bypass encompassing the transition from aprotinin to EACA (aprotinin n¼88, EACA n¼139); all other aspects including the medical team and departmental protocols remained unchanged. The primary outcome was postoperative blood loss measured as chest tube output (CTO). Secondary outcome parameters were transfusion requirements, reoperation due to bleeding, renal, vascular, and neurological complications, and inhospital mortality. Results. CTO was significantly higher in the EACA patients {aprotinin 18 (13 27) ml kg h 21, EACA 23 (15 37) ml kg h 21 [mean (inter-quartile range)], P¼0.001}, but transfusion requirements and donor exposures were not significantly different. A sensitivity analysis strengthened our finding that the increased blood loss in the EACA group was attributable to lower efficacy of EACA. There were no significant differences in the other clinical outcome measures. Conclusions. CTO was lower in aprotinin-treated patients. Nonetheless, EACA remains a suitable substitute without measurable differences in other clinical outcome criteria. Keywords: blood, transfusion; paediatric cardiac anaesthesia; surgery, cardiovascular Accepted for publication: 9 October 2012 Cardiopulmonary bypass (CPB) is often required in cardiac surgery and has potentially detrimental effects on the haemostatic system, namely activation of coagulation, inflammation, and fibrinolysis. 1 Children in particular are affected due to several specific circumstances. First, paediatric liver function and by extension haemostasis are developing systems that demonstrate marked differences compared with adults. These differences are particularly relevant in the early postnatal period. For example, the plasma levels of vitamin K-dependent factors and the contact factors are 50% of adult values. After a steep increase in the first month of life, these factors continue to increase at a steady rate and approach adult values by 6 months of chronological age, regardless of gestational age. 23 Secondly, CPB inevitably leads to haemodilution and this is particularly pronounced in small patients. CPB-related haemodilution in infants results in a reduction in coagulation factors and platelets of up to 70%, 4 and results in increased potential for haemostatic disorders. Thirdly, fibrinolysis, a long-recognized risk of CPB, 5 is more frequent among paediatric patients of young age and small size. 6 In order to reduce perioperative blood loss and transfusion, antifibrinolytic drugs have been widely used in cardiac surgery for decades and are recommended in several clinical guidelines. 7 Specifically, three drugs have been in clinical use: aprotinin, and the two lysine analogues tranexamic acid and 1-aminocaproic acid (EACA). After consultation with several health authorities, including the US Food and Drug These authors contributed equally to this manuscript. & The Author [2012]. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved. For Permissions, please journals.permissions@oup.com

2 BJA Martin et al. Administration (FDA) and Health Canada, the manufacturer of aprotinin temporarily suspended worldwide marketing of the drug due to safety concerns on November 5, On the same day, we decided to replace aprotinin with EACA as our agent of choice for the prevention of fibrinolysis-induced bleeding. In a recent review of the data on antifibrinolytic therapy in paediatric cardiac surgery, we noted that there are large variations in patients, surgical procedures, and dosing regimens within published trials. 1 Although an inverse correlation between age and both postoperative blood loss and transfusion requirement has been established in paediatric cardiac surgery, 8 no trials of antifibrinolytic agents have specifically focused on infants aged up to 1 yr. Since the haemostatic response to CPB in these patients is quite different from that of older children (lower platelet count and fibrinogen, higher blood loss and transfusion requirement), 89 we decided to investigate this particular population. Neonates were excluded and analysed in a separate study 10 because they have a higher surgical risk, blood loss, and transfusion rates. 8 The aim of this analysis was the comparison of two large cohorts of consecutive infants treated with either aprotinin during an initial 16-month period or EACA during a subsequent 26-month period. There was no gap between the two cohorts and the primary outcomes were blood loss and transfusion requirements. This comparison remains highly topical as Health Canada after a comprehensive safety review authorized aprotinin for patients undergoing coronary artery bypass grafting ( advisories-avis/_2011/2011_124-eng.php), and the European Medicines Agency also recommended lifting the suspension of aprotinin ( library/press_release/2012/02/wc pdf). Methods Study design The study was approved by the local ethics committee; the requirement for written informed consent was waived by the board. We retrospectively analysed the perioperative data of all infants (age days) undergoing cardiac surgery with CPB between July 1, 2006, and December 31, 2009 (n¼252). Only patients undergoing primary cardiac surgery were included. We excluded 22 patients because no data regarding antifibrinolytic therapy could be retrieved from the chart (10 aprotinin patients and 12 EACA patients). Until November 5, 2007, all patients were treated with aprotinin in accordance with the institutional protocol in use at the time (n¼90, referred to as the aprotinin group). On November 6, 2007, we changed our protocol by replacing aprotinin with EACA. In total, 140 patients were treated with EACA (the EACA group). All data were prospectively collected as part of a national quality assurance programme. Three patients were excluded because they could not be weaned from CPB and required transitioning to extracorporeal membrane oxygenation (aprotinin n¼2, EACA n¼1). After these exclusions, the study cohort contained data from 227 patients (aprotinin¼88, EACA¼139) (Fig. 1). Institutional protocol The institutional protocol for aprotinin (Trasylol, Bayer Pharmaceuticals, Leverkusen, Germany) consisted of a bolus of All patients (n=252) 01/07/ /12/2009 n=10 22 patients excluded due to missing documentation of antifibrinolytic medication n=12 01/07/ /11/2007 Aprotinin (n=90) 06/11/ /12/2009 EACA (n=140) n=2 3 patients excluded due to transition to ECMO n=1 Group aprotinin n=88 Group EACA n=139 Fig 1 Patients inclusion process. 616

3 Replacement of aprotinin by EACA BJA KIU (Kallikrein inhibitor unit) kg 21 administered at the beginning of CPB, followed by a continuous infusion of KIU kg 21 h 21 until chest closure KIU were added per 100 ml of the priming solution of the CPB equipment. The protocol for EACA (Aminocaproic acid, Hospira, Inc., Lake Forest, IL, USA) consisted of a bolus of 75 mg kg 21 bodyweight at the beginning and at the end of CPB, and 75 mg per 100 ml priming volume. 11 The protocols and the team of surgeons, anaesthetists, and paediatric cardiologists remained in all other aspects unchanged during the course of the study. We have previously described our anaesthetic management of these patients in detail. 12 CPB was performed using a membrane oxygenator (for children,7 kg Dideco D 901 Lilliput I; 7 20 kg Dideco D 902 Lilliput II, Sorin, Mirandola Modena, Italy) mounted on a non-pulsatile roller pump (Stöckert S5, Sorin). The priming volume of the circuit was ml. Packed red blood cells (RBC) and fresh-frozen plasma (FFP) were added to each priming volume in order to achieve a haematocrit of 30% and maintain coagulation factor levels during CPB initiation. Anticoagulation was established with an initial i.v. dose of bovine heparin of 4 mg kg 21 ; the target kaolinbased activated clotting time (ACT) was.480 s (Hemochron Signature Elite, International Technidyne Corporation, Edison, NJ, USA). Additional heparin was administered during CPB as required in order to maintain ACT.480 s. Cardiac arrest was induced by infusion of 30 ml kg 21 of cold crystalloid cardioplegic solution (Custodiol; Köhler Pharma GmbH, Alsbach, Germany). After CPB, modified ultrafiltration was performed in all patients before protamine was administered and titrated according to kaolin-based ACTs. Intra- and postoperative transfusion triggers were identical: red cell concentrates were administered at haemoglobin,14 g dl 21 in cyanotic patients and,10 g dl 21 in non-cyanotic patients. FFP was transfused at an international normalized ratio of.1.8 and platelets were transfused at a platelet count, ml 21. The indication for re-exploration in cases of postoperative bleeding was determined by the attending surgeon. Measurements We analysed patient characteristic and perioperative clinical data. All patients were assigned a Risk Adjustment for Congenital Heart Surgery (RACHS-1) score and an Aristotle basic score, 13 and these were used to assess comparability between the cohorts. The primary outcome parameter was postoperative blood loss by weight as measured by chest tube output (CTO) during the first 24 h after surgery. Secondary outcome parameters were the volume of transfused allogeneic blood products (including allogeneic products added to the CPB priming solution) during the first 24 h after surgery, subsequently postoperative transfusion requirements with exclusion of the intraoperative transfusions, and the incidence of reoperation for bleeding. Additionally, several clinical outcome criteria were monitored for safety issues. Postoperative renal dysfunction was graded according to the paediatric modified RIFLE criteria (Risk Injury Failure Loss End). 14 Urine output alone is not a good determinant of acute renal failure on the first postoperative day. The estimated creatinine clearance was calculated using the Schwartz formula 15 at 24 h after operation because postoperative creatinine levels peak at this time. 16 Echocardiography was performed on every patient on the first postoperative day and before discharge from the paediatric intensive care unit. The presence or absence of vascular thrombosis in the heart and the large vessels as diagnosed using ultrasound was documented. Neurological events (specifically seizures, stroke, and intracranial bleeding, diagnosed clinically and confirmed by CT scan or ultrasound) were also documented. Finally, all-cause in-hospital mortality was recorded. Statistical analysis Descriptive statistics are provided as means and standard deviations for normally distributed data. Medians and interquartile ranges are provided for non-normally distributed data. Categorical data are described using absolute and relative frequencies and displayed in contingency tables. Relative risks are presented with 95% confidence intervals (CI). Statistical tests for group comparisons of continuous parameters are given by the t-tests or Mann Whitney U-tests depending on the distribution of the data. Categorical variables were compared between the groups by x 2 tests, and Fisher s exact test depending on the expected cell counts of the corresponding cross-tabs. For the primary outcome, an additional sensitivity analysis was performed in order to further substantiate our findings. Therefore, CTO was log-transformed to obtain a normal distribution which renders the application of parametric analyses possible. Accordingly, group comparisons were repeated in a univariate and multivariate setting by the t-test and linear regression analysis. All tests were two-sided and conducted in an explorative manner at a 5% level of significance. The statistical analyses were performed by SPSS for Windows 19.0 statistical software package (SPSS Inc., Chicago, IL, USA) and R for statistical computing (The R Foundation for Statistical Computing, Vienna, Austria). Results The two groups were comparable with respect to all recorded patient characteristics and preoperative data (Table 1). There were no significant differences between the groups regarding intraoperative risk parameters and complexity of the operations as graded by RACHS-1 and Aristotle basic scores (Table 1). CTO at 24 h after operation was significantly lower in the aprotinin group: 18 ml kg 21 (13 27) [median (IQR)] compared with 23 ml kg 21 (15 37) in the EACA group (P¼0.001) (Table 2). This was confirmed in a sensitivity analysis performed by an additional t-test and a linear regression analysis log CTO was lower in the aprotinin group [2.9 (0.6)] 617

4 BJA Martin et al. Table 1 Perioperative data. Data are presented as incidence (%) with P-values by x 2 tests or *Fisher s exact test, mean (SD) with P-values by t-tests or median (IQR) with P-values by the Mann Whitney U-tests. EACA, 1-aminocaproic acid; CPB, cardiopulmonary bypass; DHCA, deep hypothermic cardiac arrest; RACHS-1, Risk Adjustment for Congenital Heart Surgery; POD1, postoperative day 1 Aprotinin (n588) EACA (n5139) P-value Patient characteristics Male gender 43 (49%) 81 (58%) Age (days) 137 (31-363) 141 (31-346) Height (cm) 60 (6) 61 (8) Weight (kg) 5.2 (1.6) 5.3 (1.6) Preoperative data Cyanosis 33 (38%) 47 (34%) Univentricular 13 (15%) 11 (8%) anatomy Need for intensive 23 (26%) 30 (22%) care Need for 12 (14%) 17 (12%) mechanical ventilation Treatment with 5 (6%) 7 (5%) 1.000* Prostaglandin E 2 Haemoglobin 12.3 (1.9) 12.1 (1.6) Platelets 373 (116) 372 (107) (10 3 ml 21 ) Creatinine 0.28 (0.12) 0.28 (0.09) Surgical data Duration of 181 (53) 186 (62) surgery (min) CPB time (min) 93 (42) 87 (37) DHCA 8 (9%) 6 (4%) RACHS-1 (points) 3 (2 3) 2 (2 3) Aristotle basic 8.0 ( ) 7.5 ( ) score (points) Haemoglobin POD (1.9) 14.7 (2.1) compared with the EACA group [3.2 (0.6)]. A backtransformation of this difference from the log-scale to the original scale led to the factor 0.77 [95% CI: (0.65; 0.91), P¼0.002], describing the relative reduction in the CTO. This factor increases to 0.72 [95% CI: (0.62; 0.84), P,0.001] in the regression analysis which adjusts for the potentially influencing factors listed in Table 1. The similarity of results stresses the robustness of the finding. Likewise, it also gives further evidence that groups can be validly compared as the minor; non-significant differences investigated in Table 1 only show a negligible influence on the assessment. There were no statistically significant differences with respect to reoperation for bleeding, transfusion requirements, and donor exposures, either at 24 h values or at subsequent times (Table 2). Pre- and early postoperative haematological data did not show significant differences. On postoperative day 1, the INR {aprotinin 1.19 (0.18) [mean (SD)]; EACA 1.15 (0.19), P¼0.047} and fibrinogen [aprotinin 254 (73) mg dl 21 ; EACA 314 (76) mg dl 21, P,0.001] differed between the groups (Table 3). With regard to clinical outcome parameters, there were no statistically significant differences in renal dysfunction, vascular thrombosis, neurological events, or in-hospital mortality (Table 4). Discussion The major finding of this single-centre retrospective analysis was that a protocol change from aprotinin to EACA in infants (aged days) undergoing cardiac surgery led to increased postoperative CTO. While this difference was statistically significant, we found no evidence of a clinically significant difference. This increase was not associated with an increase in allogeneic transfusions or rate of reoperation for bleeding. Further analyses did not suggest associated adverse changes for a range of major perioperative outcome parameters. Efficacy We compared two sequential treatment cohorts. These two cohorts were well matched with respect to numerous preand intraoperative characteristics. Nonetheless, we additionally performed a sensitivity analysis which strengthened our finding that the increased CTO in the EACA group was attributable to the lower efficacy of EACA and not confounding issues. In a recent systematic review of prospective trials of blood conserving measures in paediatric patients, a meta-analysis could not be performed because of the wide variation in the outcome measures used. Nevertheless, based on qualitative review, the author determined that there was sufficient evidence to conclude that the use of an antifibrinolytic decreased postoperative bleeding. 1 The assessment of the relative efficacies of aprotinin and EACA in paediatric cardiac surgery was exclusively based on a prospective trial which found that both medications similarly reduced blood loss. In contrast to our study, the patients in that prospective trial were aged between 2.7 months and 13 yr and the dosage of aprotinin was much lower. 17 Observational data are also rare in this field. Recently, an analysis of The Society of Thoracic Surgeons Congenital Heart Surgery Database suggested no difference between aprotinin and EACA in a mixed paediatric cohort. 18 Of note, the primary outcome measure in that study was the incidence of reoperation for bleeding and neither blood loss nor transfusions were assessed. Our measured CTO at 24 h in the aprotinin cohort is similar to losses reported in another study evaluating blood loss in infants (although data regarding the use of antifibrinolytic medications were not provided). 9 There is evidence that both aprotinin and EACA have antiinflammatory properties, but it remains controversial as to whether one is superior to the other in this respect Hence, it is only possible to speculate as to whether the difference in CTO between our two groups can be attributed to 618

5 Replacement of aprotinin by EACA BJA Table 2 Blood loss, reoperation for bleeding, and transfusions. Data are presented as median (IQR) or mean (SD) with P-values bythe Mann Whitney U-test or incidence (%) with P-values by the x 2 test or *Fisher s exact. CTO, chest tube output; EACA, 1-aminocaproic acid; RBC, packed red blood cells; FFP, fresh frozen plasma; pts, patients Aprotinin (n588) EACA (n5139) P-value Relative risk (95% CI) CTO (ml kg h 21 ) 18 (13 27) 23 (15 37) Reoperation for bleeding 6 (7%) 8 (6%) (0.4; 3.3) Transfusions within 24 h (including pump prime) RBC (ml kg 21 ) 71 (51 97) 68 (52 109) FFP (ml kg 21 ) 99 (72 131) 98 (67 143) Platelets (pts) 12 (14%) 23 (17%) (0.4; 1.6) Platelets (ml kg 21 ) 6 (18) 6 (15) Postoperative transfusions within 24 h RBC (pts) 12 (14%) 18 (13%) (0.5; 2.1) RBC (ml kg 21 ) 10 (30) 8 (25) FFP (pts) 24 (27%) 45 (32%) (0.6; 1.3) FFP (ml kg 21 ) 15 (28) 20 (33) Platelets (pts) 4 (5%) 5 (4%) 0.738* 1.3 (0.3; 4.6) Platelets (ml kg 21 ) 3 (15) 1 (6) Table 3 Perioperative haematological data. Data are presented as mean (SD) with P-values by t-tests. EACA, 1-aminocaproic acid; INR, international normalized ratio Aprotinin (n588) EACA (n5139) P-value Preoperative Haemoglobin 12.3 (1.9) 12.1 (1.6) Platelets (10 3 ml 21 ) 373 (116) 372 (107) INR 1.05 (0.13) 1.03 (0.14) Fibrinogen 255 (72) 271 (92) Postoperative (admission ICU) Haemoglobin 13.1 (1.7) 13.3 (1.9) Platelets (10 3 ml 21 ) 117 (48) 117 (52) INR 1.21 (0.24) 1.17 (0.16) Fibrinogen 153 (45) 191 (57) Postoperative day 1 Haemoglobin 15.1 (1.9) 14.7 (2.1) Platelets (10 3 ml 21 ) 118 (51) 133 (55) INR 1.19 (0.18) 1.15 (0.19) Fibrinogen 254 (73) 314 (76),0.001 differing anti-inflammatory effects of aprotinin and EACA. It is noteworthy that fibrinogen, which is a coagulation factor and an acute-phase protein, was also higher in EACA patients on postoperative day 1. Differential biochemical markers of inflammation like interleukins were not routinely measured during the period of investigation and the study was not designed to include closer analysis of the drainage fluid. The efficacy of any haemostatic therapy cannot be assessed solely by measurements of CTO. We also performed an analysis of transfusion requirements and rates of reoperation for bleeding. Our results showed that although statistically significant, the absolute difference of the mean CTO of 5mlkg 21 is low in relation to the mean volume of transfusion of about 175 ml 21 kg 21 (RBC, FFP, and platelets) (Table 2). We were unable to demonstrate a clinically significant impact of our protocol change on transfusion requirements or reoperation for bleeding. The benefit of aprotinin with respect to CTO might be insignificant in comparison with the large transfusion requirement (on average, double the circulating volume of the patient) over the first 24 h. Replacing aprotinin by EACA, which according to published trials potentially is less effective in its blood-sparing effect, entails the risk that physicians might have pre-emptively transfused haemostatic blood products in EACA patients. Therefore, we additionally compared haematological data throughout the perioperative course. With regard to postoperative laboratory measurement, it should be noted that all patients were transfused with FFP, which contains adult concentrations of coagulation factors. The large amount of transfused plasma ( 100 ml 21 kg 21 ) surely affects the coagulation system, but as the amount did not differ between the two groups, a similar influence on measurements should be expected. In this study, we analysed data from infants only and excluded neonates. Neonates require special consideration for several reasons: immaturity of their hepatic function resulting in a relative coagulation factor deficiency, 2 3 higher surgical risk, higher blood loss, and higher transfusion rates. 8 A post hoc comparison of this sample group with our 619

6 BJA Martin et al. Table 4 Postoperative outcome. Data are presented as incidence (%) with P-values by the x 2 test or *Fisher s exact test. EACA, 1-aminocaproic acid Aprotinin (n588) EACA (n5139) P-value Relative risk (95% CI) Renal injury 18 (21%) 19 (14%) (0.8; 2.7) Renal failure 3 (3%) 5 (4%) 1.000* 0.9 (0.2; 3.8) Vascular thrombosis 5 (6%) 10 (7%) 0.787* 0.8 (0.3; 2.2) Seizure 3 (3%) 3 (2%) 0.679* 1.6 (0.3; 7.7) Intracranial bleeding 2 (2%) 1 (1%) 0.561* 3.2 (0.3; 34.3) Stroke 3 (3%) 1 (1%) 0.301* 4.7 (0.5; 44.8) In-hospital mortality 1 (1%) 4 (3%) 0.651* 0.4 (0.1; 3.5) sample of neonates from a previous study showed that all perioperative risk factors differed considerably. 10 CTO and subsequent transfusion requirements were approximately doubled in neonates. This demonstrates again that it is crucial to group paediatric surgical patients into similar groups regarding perioperative risk if meaningful conclusions are to be reached. Clinical outcome In order to determine the relative safety of aprotinin and EACA, we analysed several major clinical outcome criteria but we could not detect any significant differences. We performed a literature search to identify any relevant previous work in order to put our results into context. This proved to be difficult as there are only a few existing studies. The majority of similar work has either focused on neonates or on mixed cohorts with wide variations in age. The incidence of the various stages of renal damage according to the RIFLE criteria did not significantly differ between the two groups. A review by Eaton 1 identified eight studies in children investigating renal outcome after aprotinin treatment. Only one of these, a retrospective analysis in children aged between 15 days and 6 yr, suggested an increased renal risk (they reported moderate impairment of tubular function). 22 All others could not prove an increased risk of renal damage after aprotinin treatment. Nonetheless, due to the small patient numbers involved, the authors could not definitively rule out increased renal risk associated with aprotinin. To date, we have not been able to identify any studies comparing EACA with control regarding the impact on renal function in paediatric cardiac surgery. Besides our own analysis of neonates, 10 only one other retrospective analysis has compared EACA with aprotinin in children (neonates up to teenagers). 23 This study found that the aprotinin-treated patients had a higher incidence of kidney injury at discharge. It is important to note that in paediatric cardiac surgery, age is an independent predictor of postoperative renal dysfunction. 24 The kidney in the infant is still developing 25 and conclusions drawn from studies of mixed paediatric populations again cannot necessarily be extended to infants. As mentioned in several publications, all antifibrinolytic therapies carry the risk of vascular thrombosis. This risk is pronounced in paediatric patients because of their small vessels, prolonged immobility, artificial shunts, low flow states, central venous catheter requirements, and high blood viscosities. 26 All patients underwent routine ultrasound of the heart and the great vessels at least twice during their postoperative course. Using this regular monitoring, we detected severe postoperative thrombotic vascular events in 6 7% of cases without a significant difference between the two groups. This rate is a little less than that observed in neonates, 10 and might be attributable to the larger vessel diameters in infants. One retrospective analysis in neonates reported a thrombosis rate of 4.6%, but it was not specified whether cardiac catheterization or ultrasound examination was routinely performed after surgery. 16 Neurological complications occurred rarely during the period of investigation and there was no significant difference between the groups. Seizures, a recently described adverse effect of the lysine analogue tranexamic acid in adults, 27 were observed in only three patients in each group (3% in the aprotinin group and 2% in the EACA group). This is within the reported range in a previous analysis of paediatric patients up to 20 kg treated with either aprotinin or tranexamic acid. 28 We were unable to identify any data regarding a specifically pro-convulsive effect of EACA in cardiac surgery in adults or children. Limitations The retrospective nature of this analysis is a weakness. We analysed the perioperative data of a large cohort of consecutive infants treated according to a strict institutional protocol. Aprotinin was replaced by EACA at a specific date and so there was no time delay between the two cohorts. Apart from the antifibrinolytic treatment all other aspects, including the team of surgeons, anaesthetists, and paediatric cardiologists and each department s protocols remained unchanged. The risk of a time-dependent bias was minimized by the additional performance of a sensitivity analysis. Although our study population was very large relative to other similar studies, we cannot exclude that the study was underpowered to detect all differences between the two groups. We restricted our cohort to infants aged between 31 and 365 days who had not undergone a previous cardiac surgical procedure in order to maximize the homogeneity of the groups with 620

7 Replacement of aprotinin by EACA BJA respect to patient and procedure factors. Accordingly, caution is required before generalizing our findings to broader paediatric cardiac surgical populations. Conclusion In this analysis of 227 consecutive infants undergoing primary cardiac surgery, replacement of aprotinin by EACA was associated with increased volume of postoperative CTO, although transfusion requirements and major clinical outcome criteria did not differ. The increased CTO in the EACA group can probably be attributed to the change in antifibrinolytic medication. Randomized controlled trials are needed to establish the safety of each antifibrinolytic medication used in paediatric cardiac surgery. In order to avoid bias, such a trial should be performed double-blinded and placebo-controlled. This need is particularly urgent in view of the fact that none of the commonly used antifibrinolytic drugs has FDA approval for their use in paediatric cardiac surgery. Declaration of interest G.W. conducted a study on a different topic supported by a grant from BAYER Vital GmbH, Leverkusen. Funding This analysis was performed solely with institutional resources. References 1 Eaton MP. Antifibrinolytic therapy in surgery for congenital heart disease. Anesth Analg 2008; 106: Andrew M, Paes B, Milner R, et al. Development of the human coagulation system in the healthy premature infant. Blood 1988; 72: Andrew M, Paes B, Milner R, et al. Development of the human coagulation system in the full-term infant. Blood 1987; 70: Kern FH, Morana NJ, Sears JJ, Hickey PR. Coagulation defects in neonates during cardiopulmonary bypass. Ann Thorac Surg 1992; 54: Gans H, Krivit W. Problems in hemostasis during open heart surgery. III. Epsilon amino caproic acid as an inhibitor of plasminogen activator activity. Ann Surg 1962; 155: Williams GD, Bratton SL, Nielsen NJ, Ramamoorthy C. Fibrinolysis in pediatric patients undergoing cardiopulmonary bypass. J Cardiothorac Vasc Anesth 1998; 12: Ferraris VA, Ferraris SP, Saha SP, et al. Perioperative blood transfusion and blood conservation in cardiac surgery: the Society of Thoracic Surgeons and The Society of Cardiovascular Anesthesiologists clinical practice guideline. Ann Thorac Surg 2007; 83: S Williams GD, Bratton SL, Riley EC, Ramamoorthy C. Association between age and blood loss in children undergoing open heart operations. Ann Thorac Surg 1998; 66: 870 5; discussion Eisses MJ, Chandler WL. Cardiopulmonary bypass parameters and hemostatic response to cardiopulmonary bypass in infants versus children. J Cardiothorac Vasc Anesth 2008; 22: Martin K, Gertler R, Liermann H, et al. Switch from aprotinin to epsilon-aminocaproic acid: impact on blood loss, transfusion, and clinical outcome in neonates undergoing cardiac surgery. Br J Anaesth 2011; 107: Ririe DG, James RL, O Brien JJ, et al. The pharmacokinetics of epsilon-aminocaproic acid in children undergoing surgical repair of congenital heart defects. Anesth Analg 2002; 94: 44 9, table of contents 12 Martin K, Breuer T, Gertler R, et al. Tranexamic acid versus epsilon-aminocaproic acid: efficacy and safety in paediatric cardiac surgery. Eur J Cardiothorac Surg 2011; 39: Lacour-Gayet F, Clarke D, Jacobs J, et al. The Aristotle score: a complexity-adjusted method to evaluate surgical results. Eur J Cardiothorac Surg 2004; 25: Akcan-Arikan A, Zappitelli M, Loftis LL, Washburn KK, Jefferson LS, Goldstein SL. Modified RIFLE criteria in critically ill children with acute kidney injury. Kidney Int 2007; 71: Schwartz GJ, Brion LP, Spitzer A. The use of plasma creatinine concentration for estimating glomerular filtration rate in infants, children, and adolescents. Pediatr Clin North Am 1987; 34: Guzzetta NA, Evans FM, Rosenberg ES, et al. The impact of aprotinin on postoperative renal dysfunction in neonates undergoing cardiopulmonary bypass: a retrospective analysis. Anesth Analg 2009; 108: Chauhan S, Kumar BA, Rao BH, et al. Efficacy of aprotinin, epsilon aminocaproic acid, or combination in cyanotic heart disease. Ann Thorac Surg 2000; 70: Pasquali SK, Li JS, He X, et al. Comparative analysis of antifibrinolytic medications in pediatric heart surgery. J Thorac Cardiovasc Surg 2012; 143: Dorman BH, Stroud RE, Wyckoff MM, et al. Differential effects of epsilon-aminocaproic acid and aprotinin on matrix metalloproteinase release in patients following cardiopulmonary bypass. J Cardiovasc Pharmacol 2008; 51: Greilich PE, Brouse CF, Whitten CW, Chi L, Dimaio JM, Jessen ME. Antifibrinolytic therapy during cardiopulmonary bypass reduces proinflammatory cytokine levels: a randomized, double-blind, placebo-controlled study of epsilon-aminocaproic acid and aprotinin. J Thorac Cardiovasc Surg 2003; 126: Greilich PE, Okada K, Latham P, Kumar RR, Jessen ME. Aprotinin but not epsilon-aminocaproic acid decreases interleukin-10 after cardiac surgery with extracorporeal circulation: randomized, double-blind, placebo-controlled study in patients receiving aprotinin and epsilon-aminocaproic acid. Circulation 2001; 104: I Ranucci M, Corno A, Pavesi M, et al. Renal effects of low dose aprotinin in pediatric cardiac surgery. Minerva Anestesiol 1994; 60: Leyvi G, Nelson O, Yedlin A, et al. A comparison of the effect of aprotinin and epsilon-aminocaproic acid on renal function in children undergoing cardiac surgery. J Cardiothorac Vasc Anesth 2011; 25: Szekely A, Sapi E, Breuer T, et al. Aprotinin and renal dysfunction after pediatric cardiac surgery. Paediatr Anaesth 2008; 18: Aperia A, Broberger O, Elinder G, Herin P, Zetterstrom R. Postnatal development of renal function in pre-term and full-term infants. Acta Paediatr Scand 1981; 70: Petaja J, Peltola K. Venous thrombosis in pediatric cardiac surgery. J Cardiothorac Vasc Anesth 1997; 11: Martin K, Wiesner G, Breuer T, Lange R, Tassani P. The risks of aprotinin and tranexamic acid in cardiac surgery: a one-year follow-up of 1188 consecutive patients. Anesth Analg 2008; 107: Breuer T, Martin K, Wilhelm M, et al. The blood sparing effect and the safety of aprotinin compared to tranexamic acid in paediatric cardiac surgery. Eur J Cardiothorac Surg 2009; 35: Handling editor: H. C. Hemmings 621

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