Aprotinin is a nonspecific serium protease inhibitor which was isolated from the bul lung

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Pro-Con Debate:   

Aprotinin Should Routinely be Used in Infants and 

Children Undergoing Complex Open Heart Surgery 

Pro 

 

Paul Reynolds M.D. 

Uma and Sujit Pandit Professor  

and Chief of Pediatric Anesthesiology 

University of Michigan 

 

Introduction 

Aprotinin is a nonspecific serine proteinase inhibitor which is isolated from the bovine 

lung. It was first introduced into clinical use in 1953 as a treatment of acute pancreatitis. (1) In 

1983, Kirklin (2) postulated that the contact of blood with the foreign surface of the oxygenator 

on the cardiopulmonary bypass (CPB) circuit initiated a cascade of events triggering an 

inflammatory response leading to “post perfusion syndrome”.  With knowledge of aprotinin’s 

ability to inhibit plasmin kallikrein he further postulated that aprotinin would block the 

inflammatory response after CPB. Uncontrolled pilot studies on patients who received aprotinin 

undergoing coronary artery bypass grafts on CPB revealed one striking feature; the patients did 

not bleed post bypass.  This led to further investigation evaluating the use of aprotinin as a 

measure to decrease post CPB transfusion requirements.  CPB can lead to postoperative bleeding 

by several mechanisms.  In addition to the effects of hemodilution and hypothermia, CPB 

activates coagulation, fibrinolytic and inflammatory pathways and impairs platelet function.  

(3)In neonates, the potential for bleeding is further increased in by the large ratio of pump prime 

volume to the patient’s blood volume, causing greater hemodilution.  Aprotinin is believed to 

prevent bleeding during and after bypass by three different mechanisms. Upon contact with the 

CPB circuit, tissue and plasma kallikrein is split to kinin.  Kinin transforms plasminogen to 

plasmin and plasmin activates neutrophils.  Aprotinin inhibits contact activation by inhibiting 

tissue and plasma kallikrein release. (4)  Secondly, aprotinin demonstrates antifibrinolytic 

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activity by increasing plasma fibrinogen and inhibiting fibrinolysis secondary to thrombin 

induced intravascular coagulation. (5) Finally, aprotinin has been shown to decreases platelet 

dysfunction and platelet aggregation after CPB.(6) 

 

Pediatric Usage 

 Post-operative bleeding in a child undergoing complex congenital heart repair has long 

been a challenge to the pediatric cardiac anesthesiologist.  Children with complex congenital 

heart defects often require multiple surgical repairs with the need for repeated sternotomies. 

Additionally, excessive hemodilution of clotting factors in the neonate, long CPB duration 

required for many complex pediatric cardiac surgical procedures, and/or institution of deep 

hypothermic circulatory arrest, all contribute to bleeding post bypass.  Long suture lines along 

the great vessels in operations such as the Norwood procedure or the Arterial Switch may also 

contribute to post bypass bleeding.  In 1987, Roysten et.al. (7) conducted the first randomized 

prospective study, comparing two groups of adults undergoing repeat median sternotomy for 

open-heart surgery. The authors reported an eightfold reduction of red blood cell (RBC) 

transfusions in the group receiving aprotinin when compared to a placebo.   

In a randomized double blind study, D’Errico et.al.(8) compared the efficacy of large 

dose aprotinin, small dose aprotinin and placebo in reducing transfusion requirements in children 

undergoing repeat open heart surgery.  The authors concluded that the use of aprotinin decreased 

the number of units of banked blood components transfused in the first 24 hours post operatively. 

In addition, time spent in the operating room was shorter in both aprotinin groups due to 

decreased time to chest wall closure.  The cost savings resulting from the reduction of blood 

transfused shorter OR time significantly reduced overall patient charges in both aprotinin groups.  

In a similar study, Miller et.al. (9) found aprotinin was effective in decreasing blood product 

exposure, shortened skin closer times, shortened durations in the intensive care unit and overall 

hospital stay, with subsequent reduction in hospital charges.  Finally, in 2006, Arnold and 

colleagues (10) performed a meta-analysis of randomized controlled trials of aprotinin involving 

children undergoing corrective or palliative cardiac surgery with CPB.  This meta- analysis 

revealed aprotinin reduced the proportion of children who received RBC or whole blood 

transfusions during cardiac surgery by 33%.  However, aprotinin had no significant effect on the 

volume of blood transfused or post-operative chest tube drainage.   

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Aprotinin is one of several antifibrinolytic drugs shown to diminish post CPB bleeding. 

The lysine analogs aminocaproic acid and tranexamic acid have also shown to be effective.  

Lysine analogs inhibit plasminogen activation to plasmin, thereby inhibiting contact activation 

during CPB and fibrinolysis.  A study in 2005 by Bulutcu, et.al.(11) compared four groups of 

children undergoing cardiac surgery on CPB for cyanotic heart disease.  The study sample 

received aprotinin alone, tranexamic acid alone, or a combination of aprotinin and tranexamic 

acid.  The placebo group had significantly greater blood loss, with more RBC and fresh frozen 

plasma (FFP) transfused when compared to the other three groups. There was no difference 

between the aprotinin and tranexamic acid groups, alone or in combination.  Although studies 

have shown that these lysine analogs can be as effective as aprotinin in preventing post 

cardiopulmonary bypass bleeding in both adults and children, aprotinin may have advantages 

lysine analogs do not exhibit.  Aprotinin may contribute to enhance hemodynamic stability in the 

postoperative period by attenuating the intensity of the inflammatory response to CPB.  It may 

also attenuate the increased peripheral vascular permeability and fibrinolysis which occurs as a 

result of CPB, and contribute to postoperative hemodynamic stability.(12) 

McDonough et.al. reviewed the use of aprotinin in children undergoing cardiopulmonary 

bypass for congenital cardiac surgery from 1993 to 2000(13).  The authors concluded that there 

was some evidence that aprotinin attenuated the inflammatory response in neonates, which led to 

a reduction in ventilator support and earlier extubation.  A meta-analysis by Murkinin in 2001 

(14) of prospective randomized placebo controlled clinical trials in North America of adults 

undergoing CABG surgery  found that aprotinin may have anti-inflammatory effects similar to 

that of methylprednisolone in decreasing systemic inflammatory responses.  In addition, 

Murkinin noted a significant decrease in the incidence of stroke in adults who receive full dose 

aprotinin versus placebo, leading the author to conclude that aprotinin may have a 

cerebroprotective effect.   

Aprotinin is also noted to be relatively safe when administered in the pediatric 

population. Jaquiss et.al. (15) noted an overall incidence of allergic reactions to aprotinin during 

pediatric cardiac surgery to be 1.6%.  First time exposure risk was 0.7%, with the risk increasing 

with the number of exposures.  Patients who developed reactions in this study showed no signs 

of hemodynamic, respiratory, renal or neurologic complications attributed to an aprotinin 

reaction. 

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With its ability to decrease blood loss and transfusions after CPB, decreasing OR time, 

ICU and hospital stays, hospital costs, and potential reduction in ventilator support and earlier 

extubation, reduction of neurologic deficits with a low incidence of allergic reactions, aprotinin 

seemed to be the ideal drug for children with complex congential heart disease undergoing CPB.  

 

The Controversy 

In 2006, Mangano et.al. (16) published an observational study involving 4374 adults 

undergoing CABG on CPB, comparing outcomes of patients receiving placebo, aprotinin, 

aminocaproic acid and tranexamic acid individually.  The authors concluded patients who 

received aprotinin were not only at twice the risk of renal failure requiring dialysis, they carried a 

55% increased risk of myocardial infarction or heart failure and a 181% increased of the risk of 

stroke when compared to the placebo or lysine analogs.  The authors noted that all 

antifibrinolytic agents reduced blood loss to the same extent.  Around the same time, another 

observational study was published by Karkouti et.al. (17) using propensity scoring to compare 

tranexamic acid with aprotinin in adults undergoing cardiac surgery requiring CPB.  The results 

of this study demonstrated a higher prevalence of renal dysfunction post bypass in the aprotinin 

group compared to the tranexamic acid group.  Renal failure became even more pronounced 

when pre-existing renal disease was present.  Again, the authors noted no difference in post 

operative bleeding between the two groups of patients.  These two studies led the FDA to release 

a public health advisory, recommending careful monitoring of patients who receive aprotinin for 

renal, cardiac and central nervous system toxicity(18). The advisory further suggested that 

aprotinin be limited to patients “where the clinical benefit of reduced blood loss is essential to 

medical management of the patient and outweighs potential risk.”   The FDA however did note 

that both studies were observational, and limited by non-randomized assignment of patients 

where the treatment was chosen by their physician as part of standard medical care.  The FDA 

concluded that the patients who had received aprotinin “may have been at a higher risk to begin 

with for these serious adverse events compared to patients receiving no treatment or treatment 

with another drug intended to decrease bleeding.”   

In an editorial, in December 2006, (19) Body et.al. noted that while Mangano and 

Karkouti had intensified discussions regarding the safety of aprotinin, their conclusions should 

be questioned because the studies were observational with uncontrolled decisions about which 

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antifibrinolytic agent was used.  The authors referenced conflicting data presented in 2004 by 

Sedrakyan et.al. (20) with regards to the effect of aprotinin on clinical outcomes following 

CABG .  Sedrakyan performed a meta-analysis of 35 randomized clinical trials from 1988-2001 

in patients undergoing CABG  who received aprotinin or placebo control.  Data from this meta-

analysis confirmed aprotinin reduced transfusion requirements relative to placebo but patients in 

both groups showed no differences in mortality, myocardial infraction or renal failure.  In 

addition, there was an associated reduced risk of stroke in the patients who received aprotinin.  

To date, no association of poor clinical outcomes following aprotinin administration in children 

has been reported. 

 

Summary 

There is a large amount of evidence in the literature that demonstrates the benefits of 

aprotinin in children undergoing repeat median sternotomy for open-heart surgery.  These 

benefits include a decrease in the amount of blood lost and transfused, shorter OR, ICU and 

hospital stays, and decreased cost. Furthermore, there is evidence that suggests that decrease the 

inflammatory response to surgery and CPB leasing to improved outcomes including more 

cardiovascular stability, requirement for fewer inotropes, reduction in ventilator support, earlier 

extubation, and reduction of neurologic deficits.  While the lysine analogs may be as effective at 

decreasing blood loss after CPB, they do not demonstrate the additional beneficial anti-

inflammatory effects of aprotinin.  Further study on this high risk pediatric population with 

regards to the use of aprotinin is warranted and encouraged.  Prospective randomized studies 

evaluating outcomes of the various antifibrinolytic therapies available will allow us to rationally 

decide the cost effectiveness of these drugs and their impact on patient outcomes.  Until such 

data become available, the continued use of aprotinin for repeat or complex open heart surgery in 

children is well supported by existing evidence. 

 

References 

 

1. 

Bonney SL, Maenpaa SC. Investigator's brochure.  BAY a 0128 Aprotinin (trasylol): 

Miles Inc., Pharmaceutical Division, 1993. 

2. 

Kirklin JW, Barrat-Boyes BG. Cardiac Surgery New York: John Wiley & Sons, 1986. 

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3. 

Nakahara M. Inhibitory effect of aprotinin and gabexate mesilate on human plasma 

kallikrein. Arzneimittel-Forschung 1983;33:969-71. 

4. 

Nordstroem S, Blombaeck M, Olsson P, et a. Experimental investigations with proteinase 

inhibitors. Acta Chir Scan (Suppl) 1967;378:33-40. 

5. 

Reuter HD, Czybulka I, Zanger I. The influence of Trasylol on platelet aggregation, 

platelet retention and Factor 3 availability. In: Ludwig FK, ed. Blutgerinnung und 

Gefaesswand Schattauer, Stuttgart, 1981:269-78. 

6. 

Levy JH. Pharmacologic preservation of the hemostatic system during cardiac surgery. 

Annals of Thoracic Surgery 2001;72:S1814-20. 

7. 

Royston D, Bidstrup BP, Taylor KM, Sapsford RN. Effect of aprotinin on need for blood 

transfusion after repeat open-heart surgery. Lancet 1987;2:1289-91. 

8. 

D'Errico CC, Shayevitz JR, Martindale SJ et.al.. The efficacy and cost of aprotinin in 

children undergoing reoperative open heart surgery. Anesthesia & Analgesia 

1996;83:1193-9. 

9. 

Miller BE, Tosone SR, Tam VK et.al.. Hematologic and economic impact of aprotinin in 

reoperative pediatric cardiac operations. Annals of Thoracic Surgery 1998;66:535-40; 

discussion 41. 

10. 

Arnold DM, Fergusson DA, Chan AK et.al.. Avoiding transfusions in children 

undergoing cardiac surgery: a meta-analysis of randomized trials of aprotinin. Anesthesia 

& Analgesia 2006;102:731-7. 

11. 

Bulutcu FS, Ozbek U, Polat B et.al.. Which may be effective to reduce blood loss after 

cardiac operations in cyanotic children: tranexamic acid, aprotinin or a combination? 

Paediatric Anaesthesia 2005;15:41-6. 

12. 

Wachtfogel YT, Hack CE, Nuijens JH et.al.. Selective kallikrein inhibitors alter human 

neutrophil elastase release during extracorporeal circulation. American Journal of 

Physiology 1995;268:H1352-7. 

13. 

McDonough J, Gruenwald C. The use of aprotinin in pediatric patients: a review. Journal 

of Extra-Corporeal Technology 2003;35:346-9. 

14. 

Murkin JM. Attenuation of neurologic injury during cardiac surgery. Annals of Thoracic 

Surgery 2001;72:S1838-44. 

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15. 

Jaquiss RD, Ghanayem NS, Zacharisen MC et.al.. Safety of aprotinin use and re-use in 

pediatric cardiothoracic surgery. Circulation 2002;106:I90-4. 

16. 

Mangano DT, Tudor IC, Dietzel C et.al.. The risk associated with aprotinin in cardiac 

surgery.[see comment]. New England Journal of Medicine 2006;354:353-65. 

17. 

Karkouti K, Beattie WS, Dattilo KM et.al.. A propensity score case-control comparison 

of aprotinin and tranexamic acid in high-transfusion-risk cardiac surgery.[see comment]. 

Transfusion 2006;46:327-38. 

18. 

FDA. Aprotinin Injection (marketed as Trasylol) Public Health Advisory, 2006. 

19. 

Body SC, Mazer CD. Pro: Aprotinin has a good efficacy and safety profile relative to 

other alternatives for prevention of bleeding in cardiac surgery.[see comment]. 

Anesthesia & Analgesia 2006;103:1354-9. 

20. 

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. Journal of Thoracic & Cardiovascular Surgery 2004;128:442-

8.