Eur J Cardiothorac Surg 2009;35:167-171. doi:10.1016/j.ejcts.2008.09.038
Copyright © 2009, European Association for Cardio-thoracic Surgery. Published by Elsevier. All rights reserved.
The blood sparing effect and the safety of aprotinin compared to tranexamic acid in paediatric cardiac surgery
Tamás Breuera,d,
Klaus Martina,*,
Markus Wilhelma,
Gunther Wiesnera,
Christian Schreiberb,
John Hessc,
Rüdiger Langeb,
Peter Tassania
a Institute of Anaesthesiology, German Heart Centre, Clinic at the Technical University Munich, Lazarettstr. 36, 80636 Munich, Germany
b Department of Cardiovascular Surgery, German Heart Centre, Clinic at the Technical University Munich, Munich, Germany
c Department of Paediatric Cardiology and Congenital Heart Defects, German Heart Centre, Clinic at the Technical University Munich, Munich, Germany
d Department of Cardiology, Semmelweis University, Budapest, Hungary
Received 6 June 2008;
received in revised form 7 August 2008;
accepted 18 September 2008.
* Corresponding author. Tel.: +49 89 1218 4611; fax: +49 89 1218 4613. (Email: martin{at}dhm.mhn.de).
 |
Abstract
|
|---|
Objective: Recently, the safety of aprotinin administration during open-heart surgery has been debated. The aim of the study was to compare the blood sparing effect and the side effects of aprotinin and tranexamic acid in paediatric cardiac surgery patients. Methods: Perioperative data of 199 consecutive patients weighing less than 20 kg undergoing open-heart cardiac surgery were prospectively collected between September 2005 and June 2006. During the first 5 months, 85 patients received aprotinin (group A); in the next 5 months, 114 patients were treated with tranexamic acid (group T). Except for antifibrinolytic therapy, the anaesthesiological and surgical protocols remained unchanged. Postoperative complications and in-hospital and 1-year mortality were considered as outcome parameters. Results: The descriptive parameters and the intraoperative parameters were well comparable in the two groups. The blood loss was significantly lower in group A compared to group T at 6 h [55 (35–82.5) vs 70 (45–100) ml, p
= 0.031], but not at 12 and 24 h after operation. The incidence [9 (11%) vs 25 (22%), p
= 0.035] and the amount of red blood cell transfusion during the first 24 h after surgery were also significantly lower in group A (0.1 ± 0.4 vs 0.3 ± 0.6 unit, p
= 0.036). There were significantly less rethoracotomies in group A [2 (2.4%) vs 11 (9.6%), p
= 0.039]. We found no difference in the incidence of the postoperative complications and in-hospital and 1-year mortality. There was a tendency for a higher incidence of seizures in group T [4 (3.5%) vs 0 (0%), p
= 0.14]. Conclusions: Aprotinin administration bears no additional risks compared to tranexamic acid and it has a stronger blood sparing effect in paediatric cardiac surgery. There were fewer rethoracotomies and less postoperative red blood cell transfusion in patients who received aprotinin.
Key Words: Congenital heart defects • Paediatric cardiac surgery • Antifibrinolytics • Blood transfusion • Morbidity • Mortality
|
1. Introduction
|
|---|
Aprotinin is a serine protease inhibitor, inhibits kallikrein and the conversion of plasminogen to plasmin. Due to this inhibitory effect on fibrinolysis and other inflammatory cascade reactions, it has been extensively used during cardiac surgery to diminish blood loss and to suppress inflammatory response to cardiopulmonary bypass (CPB) [1]. The possible deleterious effects of aprotinin on renal function have been known, but recently a strong and consistent negative mortality trend associated with aprotinin in high-risk patients has been reported [2]. Lysine analogues, such as tranexamic acid and 
-aminocaproic acid, are now widely used to reduce blood loss, however, their blood sparing effect was often inferior to that of aprotinin [3]. Furthermore, the safety of lysine analogues has not been studied to the same extent as that of aprotinin. We previously found that tranexamic acid was associated with adverse events after valve surgery in adult patients [4].
In paediatric heart surgery, antifibrinolytic drugs have great importance in blood sparing strategies and thus in avoiding blood transfusion and related complications [5]. The blood sparing effect of aprotinin and tranexamic acid in children has been shown [1,6], but only few data are available regarding their safety [7].
At our institution, aprotinin has been used in almost every child undergoing cardiac surgery with CPB for many years. As a consequence of the serious concerns about the safety of aprotinin in adults, we decided to completely stop using aprotinin and use tranexamic acid instead as the antifibrinolytic agent of choice during adult and paediatric cardiac surgery. Similarly to our previous study in adults [4], the aim of the study was to compare the blood loss and the outcome data of a 5-month period of tranexamic acid administration with the data of the preceding 5 months of aprotinin administration in consecutive paediatric patients undergoing cardiac surgery with extracorporeal circulation.
|
2. Methods
|
|---|
The study was approved by the ethical committee of the Technical University Munich (Germany); the need for parental informed consent was waived by the board. We consecutively analysed the perioperative data of all children weighing less than 20 kg undergoing cardiac surgery with CPB between September 2005 and June 2006 (n
= 225). Data were prospectively collected as part of the quality assurance of the clinic. We excluded patients who did not receive any antifibrinolytic therapy, or the administered dose of the antifibrinolytic agent was not sufficient according to our institutional protocol or patients who received multiple agents (n
= 26). After exclusions, the study cohort contained data of 199 consecutive patients. If a patient was reoperated for non-bleeding reasons during the same admission, only data from the first operation were included in the analysis.
Until January 2006, the patients undergoing cardiac surgery with CPB were treated with aprotinin (Trasylol; Bayer, Leverkusen, Germany) according to the institutional protocol (group A). The protocol consisted of a bolus of 50 000 KIU/kg aprotinin administered at the beginning of CPB, followed by a continuous infusion of 10 000 KIU/kg/h until chest closure; 100 000 KIU/100 ml were added to the prime of the CPB equipment. From February 2006 on, aprotinin was completely replaced by tranexamic acid (Cyklokapron; Pfizer, Karlsruhe, Deutschland) (group T). Tranexamic acid was administered as boli of 50 mg/kg at the beginning and at the end of CPB, and 100 mg/100 ml were added to the prime of the CPB equipment.
In all other aspects, the surgical and anaesthesiological protocols remained unchanged. Patients were anaesthetised with standard balanced or total intravenous anaesthesia. A standard CPB setting was used. After cross-clamping of the aorta, 40 ml/kg of cold crystalloid cardioplegic solution (Bretschneider = Custodiol; Köhler Chemie, Alsbach-Hähnlein, Germany) was used for cardiac arrest. Postoperative treatment was performed by paediatric cardiologists at the paediatric intensive care unit (ICU). Transfusion triggers were a haemoglobin level <14 g/dl in cyanotic patients and <10 g/dl in non-cyanotic patients, or if a patient showed clinical signs indicating the need for a higher oxygen supply. Rethoracotomy for bleeding was indicated by the attending surgeon.
We compared the perioperative data of the patients from the 5-month period of using tranexamic acid (group T, n
= 114) with the data of patients from the preceding 5 months of aprotinin administration (group A, n
= 85). We analysed the main demographic data, the data of medical history and the main intraoperative data. Postoperative blood loss was measured as chest-tube output at 6, 12 and 24 h after surgery. The amount of transfused allogeneic blood products and the need for rethoracotomy were also recorded.
Postoperative renal injury was defined according to the paediatric modified RIFLE criteria (creatinine clearance decreased by 50%, [8]). The estimated creatinine clearance was calculated using the Schwartz et al. formula [9]. Renal failure was defined as need for postoperative dialysis. Postoperative low cardiac output syndrome was defined as need for high dose inotropic support at the end of surgery (at least of 0.1 epinephrine µg/kg/min). Neurological events, such as new seizure or other neurological events, e.g. cerebral oedema, intracranial bleeding, were clinically diagnosed and if possible confirmed by CT scan. In-hospital mortality was recorded. All-cause mortality was also assessed 1 year after surgery. Usually, the patients took part in a routine examination 1 year after surgery. If necessary, the patients’ cardiologists were contacted.
Continuous parameters were compared between the groups by Mann–Whitney U test; for categorical variables chi-square test or Fisher's exact test were used as appropriate. For chi-square analysis, the effective total sample size to give a power level of 0.8 (
= 0.05, estimated effect size = 0.2, d.f. = 1) is 197 (GPOWER for MS-DOS, Franz Faul & Edgar Erdfelder, Bonn, Germany). The difference in 1-year mortality between the treatment groups was assessed by Mantel–Cox log-rank test. The results of the two-sided tests were considered significant if the p value was less than 0.05. The statistical analyses were performed by SPSS for Windows 15.0 statistical software package (SPSS Inc., Chicago, IL, USA).
|
3. Results
|
|---|
The descriptive parameters were well comparable in the two groups; no statistically significant difference was found (Table 1
). The preoperative medical history and the laboratory values of the patients were also similar. There was no difference in the complexity of the operations graded according to the RACHS classification system [10] and in the durations of CPB and aorta cross-clamp. We found no significant difference in the intraoperative transfusion of blood products (Table 2
).
The postoperative blood loss was significantly lower in group A compared to group T at 6 h after surgery, but the difference did not reach the level of significance at the subsequent time-points (Fig. 1
). The incidence [9 (11%) vs 25 (22%), p
= 0.035] and the amount of red blood cell (RBC) transfusion during the first 24 h after surgery were also significantly lower in group A (Table 2). The postoperative haemoglobin values were comparable (14.7 ± 2.6 g/l in group T vs 14.9 ± 2.3 g/l in group A; p
= 0.69).
View larger version (18K):
[in this window]
[in a new window]
|
Fig. 1. Postoperative blood loss of the patients. Boxes represent median and interquartile range; whiskers show the largest and smallest observed values closer than 1.5 box lengths. *p
< 0.05.
|
|
There were significantly more rethoracotomies and a tendency for a higher incidence of seizures in group T (Table 3
). We found no difference in the incidences of cardiac and renal complications and in in-hospital mortality between the groups (Table 3). Follow-up information could be assessed in 79.8% and 78.8% of the patients in group T and group A, respectively. Six patients (6.6%) died in group T and 4 (6.0%) in group A during 1 year after surgery (p
= 0.88).
|
4. Discussion
|
|---|
We analysed the perioperative data of a consecutive patient cohort of 10 months. The consequent treatment with one of the examined antifibrinolytic agents during the first and second halves of the study period offered us the opportunity to create unselected treatment groups of our consecutive patients. Thus the risk of bias related to the patient selection was minimised, contrary to observational studies [11]. The propensity-adjusted multivariable logistic regression used by recent studies has been extensively discussed and considered as only ‘hypothesis generating’ [12]. Based on the enrolment of unselected consecutive patients in the two treatment groups and the numerous comparable demographic and preoperative data, we assumed that the unmeasured underlying variables of the patients were also similar.
We enrolled a comprehensive number of patients in our study, which exceeded the sample size of the randomised trials (25–180 patients) included in a recent meta-analysis [13]. We found that postoperative blood loss was significantly lower in group A than in group T at 6 h after surgery. Although the difference in bleeding was not significant in the whole examined period, the advantage of aprotinin apparently resulted in a significantly lower rate of rethoracotomies. Rethoracotomy is one of the most common complications of postoperative bleeding after cardiac surgery and bears high risks for adverse outcome and prolonged hospital stay [14]. The increased rate of rethoracotomies in group T may also have contributed to the lesser difference in blood loss from the 12th postoperative hour on.
Consistently, the postoperative transfusion of RBCs was also significantly lower in group A. Furthermore, the number of patients transfused postoperatively was more than double after tranexamic acid treatment than after aprotinin. Our findings are partly in conflict with the results of a meta-analysis of 12 randomised trials [13]. Interestingly, the studies included in the meta-analysis compared the effect of aprotinin to placebo/no treatment group, whereas we compared it to another effective treatment. Risks of transfusion in adults are well known; in critically ill children, independent associations of blood transfusion with prolonged intensive care and mortality have also been proven recently [5].
Among the possible side effects of aprotinin, renal injury has been extensively studied, since aprotinin has a high affinity to the renal tissue. The role of aprotinin in the development of postoperative renal complications is still controversial [3,15]. Nevertheless, some possible effects of aprotinin on renal function have been both experimentally and clinically described, e.g. decreased kinin synthesis, diminished renal blood flow and glomerular filtration rate, and reversible tubular overload [16,17].
Regarding the safety of aprotinin in paediatric population few data have been published. We neither found differences between the groups in the incidences of postoperative renal injury and failure, nor regarding other organ damages and mortality. A recent large, retrospective analysis has come to the same conclusions [7]. They used a similar definition for renal dysfunction as we did, but they reported a lower incidence (6%) of that compared to our cohort. This can be related to the higher age of their patients. Although their study design is similar to this one regarding that there was no selection bias for the use or non-use of aprotinin, the authors remind us of the limitations of an unintentional time-based selection bias. This could only have slightly affected our results due to the much shorter examination period. Another recent, propensity-adjusted study of a 2-year patient cohort found that, despite the higher incidences of renal complications in the aprotinin group, the drug had no independent role in renal impairment [11]. These two studies taken together with the present study complement each other well regarding the methodological strengths and limitations. Thus they generate a considerable amount of proof that aprotinin administration is safe in paediatric cardiac surgery.
We found an increased susceptibility to seizures after tranexamic acid treatment, similarly to the significant finding in adults [4]. An epileptogenic effect has already been described experimentally after topical [18,19], and intravenous [18] application of tranexamic acid; and also clinically after accidental intrathecal application [20]. Tranexamic acid diminishes cerebral blood flow [21] most likely by arterial vasoconstriction [22]. Besides, the antagonistic effect of tranexamic acid on GABA receptors has also been identified as a possible mechanism of provoking convulsions [23]. The tendency of increased incidence of postoperative seizure in group T, therefore, can be explained by the combination of these deleterious effects with the microemboli caused by congenital heart surgery [24]. In adults, tranexamic acid administration was related to a significantly higher rate of seizures after valve and high-risk surgery [4]. Nevertheless, cerebroprotective effect has already been attributed to aprotinin [15]. This tendency is alarming since postoperative seizure in early infancy has been related to worse neurodevelopmental outcome [25].
|
5. Limitations
|
|---|
Our study compared data of two chronologically close patient cohorts. Therefore the risk of unrecognised changes in practice is reduced to a minimum, but it cannot be excluded completely. However, due to the study design and the fact that the known parameters were comparable, we assumed that the groups matched well and the unknown variables were also comparable.
Our observational study enrolled a comprehensive number of consecutive patients. The sample size was larger than in most of the randomised trials in this field. However, we cannot exclude that the study did not have enough power to detect all the differences between the treatment groups. Carefully designed, randomised, controlled trials are needed to explore the possible side effects of the different antifibrinolytic treatments in paediatric cardiac surgery and to be able to propose recommendations regarding the best clinical practice.
|
6. Conclusions
|
|---|
In a consecutive cohort of 199 paediatric patients weighing less than 20 kg undergoing open-heart surgery, we found that aprotinin treatment was more effective than tranexamic acid regarding the postoperative blood loss and blood transfusion. Consistently, there were also significantly less rethoracotomies in the former treatment group. We found no difference in the incidences of cardiac and renal complications, and in in-hospital and 1-year mortality. There was a tendency for higher seizure rates after tranexamic acid treatment. According to our results, aprotinin treatment bears no additional risks and its efficiency is superior to that of tranexamic acid in this patient population. Tranexamic acid is an applicable alternative for aprotinin, however, with some concerns.
|
Appendix A
|
|---|
Conference discussion
Dr P. Pouard (Paris, France): Unfortunately, as you know, this study comes a little bit later, like all the others reports. Since your study we have had two reports in anaesthesia analgesia, and both of them, randomised and prospective, show the same that you have shown. In other words, it means that aprotinin was very safe in paediatric patients and that we have never seen any renal failure even after thousands of patients, neither increased mortality. But unfortunately, the company, Bayer, has never taken into consideration the paediatric patients. And this is probably the reason why we are not allowed to use it any more even if no side effects have been shown.
So, for me, the most important address in your study is not about aprotinin, it is about tranexamic acid. Because we have not read any trial or report about safety of tranexamic acid. And this is dangerous, because people are promoting tranexamic acid for all the patients to replace aprotinin, but without any proof of safety.
The second point, and for me it's very important for neonates, is the risk of seizures. Of course, it has not been tested as significant, but it's four cases versus zero. And I have recently heard in some centres in France, in adult as well as in paediatric cardiac surgery, more seizures after high doses of tranexamic acid. And I’m sure that we will also see more and more thrombosis. When you look at the literature, we have thousands of patients studied with aprotinin and only hundreds of patients with tranexamic acid, and for tranexamic acid and children, nearly nothing, five or six reports, no randomised paper, and finally no serious studies.
So, this is the reason why I think that, first, your study is very interesting because of the number of unselected and consecutive patients, even if it is not randomised. And second because you highlight the risks of tranexamic acid.
Dr Tassani: I could make a comment on this last point on tranexamic acid because we did evaluate, the same time period, the adult patients, which is at the time of publication, about 1200 patients, also consecutive patients, which we operated in this period, and their seizures had reached a level of significance. It means that it was highly significant and that in these adult patients tranexamic acid causes more seizures than aprotinin. In the paediatric group, there were only four patients, so it did not reach a level of significance.
Dr Pouard: But under the neurological point of view, aprotinin has always been seen as a protection, much more than the cause of seizures.
|
Footnotes
|
|---|
Presented at the 22nd Annual Meeting of the European Association for Cardio-thoracic Surgery, Lisbon, Portugal, September 14–17, 2008.
|
References
|
|---|
- Mössinger H, Dietrich W, Braun SL, Jochum M, Meisner H, Richter JA. High-dose aprotinin reduces activation of hemostasis, allogeneic blood requirement, and duration of postoperative ventilation in pediatric cardiac surgery. Ann Thorac Surg 2003;75:430-437.[Abstract/Free Full Text]
- Fergusson DA, Hébert PC, Mazer CD, Fremes S, MacAdams C, Murkin JM, Teoh K, Duke PC, Arellano R, Blajchman MA, Bussières JS, Côté D, Karski J, Martineau R, Robblee JA, Rodger M, Wells G, Clinch J, Pretorius R, BART Investigators A comparison of aprotinin and lysine analogues in high-risk cardiac surgery. N Engl J Med 2008;358:2319-2331.[Abstract/Free Full Text]
- Brown JR, Birkmeyer NJ, O’Connor GT. Meta-analysis comparing the effectiveness and adverse outcomes of antifibrinolytic agents in cardiac surgery. Circulation 2007;115:2801-2813.[Abstract/Free Full Text]
- Martin K, Wiesner G, Breuer T, Lange R, Tassani P. Risks of aprotinin and tranexamic acid in cardiac surgery: 1-year follow-up of 1188 consecutive patients. Anesth Analg; (2008) doi:10.1213/ane06013e318184bc20.
- Kneyber MC, Hersi MI, Twisk JW, Markhorst DG, Plötz FB. Red blood cell transfusion in critically ill children is independently associated with increased mortality. Intensive Care Med 2007;33:1414-1422.[CrossRef][Medline]
- Reid RW, Zimmerman AA, Laussen PC, Mayer JE, Gorlin JB, Burrows FA. The efficacy of tranexamic acid versus placebo in decreasing blood loss in pediatric patients undergoing repeat cardiac surgery. Anesth Analg 1997;84:990-996.[Abstract]
- Backer CL, Kelle AM, Stewart RD, Suresh SC, Ali FN, Cohn RA, Seshadri R, Mavroudis C. Aprotinin is safe in pediatric patients undergoing cardiac surgery. J Thorac Cardiovasc Surg 2007;134:1421-1426.[Abstract/Free Full Text]
- 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;71:1028-1035.[CrossRef][Medline]
- 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;34:571-590.[Medline]
- Jenkins KJ, Gauvreau K, Newburger JW, Spray TL, Moller JH, Iezzoni LI. Consensus-based method for risk adjustment for surgery for congenital heart disease. J Thorac Cardiovasc Surg 2002;123:110-118.[Abstract/Free Full Text]
- Székely A, Sápi E, Breuer T, Kertai, MD, Bodor G, Vargha P, Szatmári A. Aprotinin and renal dysfunction after pediatric cardiac surgery. Paediatr Anaesth 2008;18:151-159.[Medline]
- Body SC, Mazer CD. Pro: aprotinin has a good efficacy and safety profile relative to other alternatives for prevention of bleeding in cardiac surgery. Anesth Analg 2006;103:1354-1359.[Free Full Text]
- Arnold DM, Fergusson DA, Chan AK, Cook RJ, Fraser GA, Lim W, Blajchman MA, Cook DJ. Avoiding transfusions in children undergoing cardiac surgery: a meta-analysis of randomized trials of aprotinin. Anesth Analg 2006;102:731-737.[Abstract/Free Full Text]
- Dacey LJ, Munoz JJ, Baribeau YR, Johnson ER, Lahey SJ, Leavitt BJ, Quinn RD, Nugent WC, Birkmeyer JD, O’Connor GT, Northern New England Cardiovascular Disease Study Group Reexploration for hemorrhage following coronary artery bypass grafting: incidence and risk factors. Arch Surg 1998;133:442-447.[Abstract/Free Full Text]
- Sedrakyan A, Treasure T, Elefteriades JA. Effect of aprotinin on clinical outcomes in coronary artery bypass graft surgery: a systematic review and meta-analysis of randomized clinical trials. J Thorac Cardiovasc Surg 2004;128:442-448.[Abstract/Free Full Text]
- Hörl WH. Aprotinin and renal function in patients undergoing cardiac surgery. Br J Anaesth 2000;84:3-5.[Free Full Text]
- Wells PS. Safety and efficacy of methods for reducing perioperative allogeneic transfusion: a critical review of the literature. Am J Ther 2002;9:377-388.[CrossRef][Medline]
- Pellegrini A, Giaretta D, Chemello R, Zanotto L, Testa G. Feline generalized epilepsy induced by tranexamic acid (AMCA). Epilepsia 1982;23:35-45.[Medline]
- Schlag MG, Hopf R, Zifko U, Redl H. Epileptic seizures following cortical application of fibrin sealants containing tranexamic acid in rats. Acta Neurochir (Wien) 2002;144:63-69.[CrossRef][Medline]
- de Leede-van der Maarl MG, Hilkens P, Bosch F. The epileptogenic effect of tranexamic acid. J Neurol 1999;246:843.[CrossRef][Medline]
- Tsementzis SA, Meyer CH, Hitchcock ER. Cerebral blood flow in patients with a subarachnoid haemorrhage during treatment with tranexamic acid. Neurochirurgia (Stuttg) 1992;35:74-78.[Medline]
- Iplikcioglu AC, Berkman MZ. The effect of short-term antifibrinolytic therapy on experimental vasospasm. Surg Neurol 2003;59:10-17.[CrossRef][Medline]
- Furtmüller R, Schlag MG, Berger M, Hopf R, Huck S, Sieghart W, Redl H. Tranexamic acid, a widely used antifibrinolytic agent, causes convulsions by a gamma-aminobutyric acid(A) receptor antagonistic effect. J Pharmacol Exp Ther 2002;301:168-173.[Abstract/Free Full Text]
- O’Brien JJ, Butterworth J, Hammon JW, Morris KJ, Phipps JM, Stump DA. Cerebral emboli during cardiac surgery in children. Anesthesiology 1997;87:1063-1069.[CrossRef][Medline]
- Rappaport LA, Wypij D, Bellinger DC, Helmers SL, Holmes GL, Barnes PD, Wernovsky G, Kuban KC, Jonas RA, Newburger JW, Boston Circulatory Arrest Study Group Relation of seizures after cardiac surgery in early infancy to neurodevelopmental outcome. Circulation 1998;97:773-779.[Abstract/Free Full Text]
This article has been cited by other articles:
|
|
|
|
 
J. M. Murkin, F. Falter, J. Granton, B. Young, C. Burt, and M. Chu
High-Dose Tranexamic Acid Is Associated with Nonischemic Clinical Seizures in Cardiac Surgical Patients
Anesth. Analg.,
February 1, 2010;
110(2):
350 - 353.
[Abstract]
[Full Text]
[PDF]
|
|
|
Top
Abstract
1. Introduction
