The use of aprotinin in pediatric cardiac surgery: should we bid ‘good riddance’ or are we throwing out the baby with the bath water?

Appearing in this issue of the journal is an article describing the use of aprotinin in neonates undergoing cardiac surgery (1). The article describes a prospective, randomized, placebo-controlled study of high-dose aprotinin in 26 neonates. The rationale for the study was that neonates are at increased risk for bleeding and activation of inflammatory responses after cardiopulmonary bypass and that aprotinin may be efficacious in mitigating both processes (2,3). The primary outcome measure was duration of postoperative mechanical ventilation and the secondary outcomes included total blood product exposure and length of ICU and hospital admission. The data were analyzed after enrollment was halted due to FDA concerns about the safety of aprotinin. There was no difference between groups in any outcome measure, although patients treated with aprotinin received a smaller volume of platelets and there appeared to be a trend toward reduced total blood product exposure in this group. Twentyfour hours after surgery patients in both groups had a significant rise in serum creatinine levels from baseline. Creatinine levels decreased after 24 h and normalized by 72 h in both the aprotinin and control groups. No allergic reactions to aprotinin administration were detected. Aprotinin was discovered in 1930 at the University of Munich, Germany. Initially isolated from bovine lung tissue, aprotinin was first used in 1959 in Germany for the treatment of pancreatitis (4). In 1994, Trasylol (Bayer Pharmaceuticals Corporation, West Haven, CT, USA) was launched in the USA for blood conservation in adults undergoing coronary artery bypass graft surgery on cardiopulmonary bypass. Since then more than 1500 papers on aprotinin use have been published, primarily in adults. In pediatrics, there are insufficient data to determine whether aprotinin is safe and efficacious. Safety concerns with the drug primarily involve thrombosis, anaphylaxis, and renal effects. Although there are cases of thrombosis in children receiving aprotinin, the largest pediatric review identified no increased risk of thrombosis in 865 exposures (5). Anaphylaxis may occur less commonly than in adults (6), possibly related to immaturity of the neonatal immune system. The rate of adverse reactions has been reported to be 1.16% of total exposures and 1.6% in reexposures (5). The minimum time frame between exposures required to preclude anaphylaxis has not been determined, but many practitioners avoid reexposure within 6 months. With respect to adverse renal effects, eight studies have reported renal outcomes after aprotinin use and do not indicate an increased risk of renal failure related to aprotinin treatment. The consensus at a symposium held in 1997 on the use of aprotinin in pediatrics was that aprotinin appeared to be safe. More recent studies have concurred, although no studies have been performed that are adequately powered to determine safety in pediatrics (7). The consensus at the 1997 symposium was that aprotinin has possible efficacy in reducing blood and blood product requirements, particularly in children undergoing repeat procedures (8). A more Correspondence to: Gregory B. Hammer, Departments of Anesthesia and Pediatrics, Stanford University School of Medicine, Stanford, CA, USA (email: ham@stanford.edu) Pediatric Anesthesia 2008 18: 809–811 doi:10.1111/j.1460-9592.2008.02717.x