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Objective: To determine how the anti-inflammatory properties of aprotinin impact on postoperative complications in children undergoing the Fontan procedure., Methods: We included all patients between 14 months and 18 years (n=56) undergoing a Fontan operation at our institution between January 2005 and June 2009. The study group (n=29) included patients from January 2005 through December 2007 all of whom received aprotinin. The control group (n=27) included all patients from January 2008 through June 2009 who did not receive aprotinin. We reviewed all medical records and collected preoperative, intraoperative and postoperative data. Duration and volume of chest tube drainage were the primary outcome measures., Results: Of the 20% of patients who had postoperative arrhythmias, multivariate logistic regression analysis demonstrated only aprotinin was associated with significantly decreased postoperative arrhythmias (P=0.01). Renal function and fenestration or Fontan thrombosis did not differ significantly; there was no statistically significant difference in volume or duration of chest tube drainage. Median duration of chest tube drainage was 7 days in the aprotinin group and 8 days for patients who did not receive aprotinin (P=0.36)., Conclusion: The anti-inflammatory properties of aprotinin may be protective against postoperative arrhythmias. Aprotinin does not confer increased risks of prolonged chest tube drainage, renal dysfunction or thrombosis in patients undergoing the Fontan procedure.

Aprotinin (Trasylol) is a serine protease inhibitor, isolated from bovine lung that initially was marketed for the treatment of pancreatitis. In the mid 1980s, reports of its ability to decrease hemorrhaging after cardiopulmonary bypass surgery introduced the drug to the realm of cardiac surgery. Unfortunately, its introduction into this arena was followed by the publication of multiple studies and case reports that blamed aprotinin for poor outcomes in the form of early graft closure. More than 17 years have passed since the initial article describing the use of aprotinin during cardiopulmonary bypass, and with time there has been a significant increase in scientific knowledge and clinical experience. Interestingly, modern literature does not support the dogma that aprotinin is a procoagulant. Aprotinin increases the activated partial thromboplastin time (aPTT), as well as the kaolin- and celite-activated clotting time (ACT), regardless of heparin. Aprotinin, because of its ability to inhibit kallikrein, has been found to decrease thrombin antithrombin III complexes, fibrin-split products, fibrinopeptide 1+2, prothrombin fragments, and all markers of thrombin formation. Some authors have suggested that it may have a synergistic effect with heparin to ensure graft patency. Anticoagulation monitoring during the use of aprotinin also has been developed based on early studies. Aprotinin administration does influence the results of various ACT tests, and consequently different methods of testing anticoagulation have been developed. Researchers have demonstrated that the celite ACT is not "artificially" prolonged in the presence of heparin and aprotinin, rather the kaolin ACT is "artificially" shortened. This article will review the scientific literature with regard to aprotinin's anticoagulatory effects and review the current recommendations for hemostasis monitoring during the use of aprotinin.

Background: Hypersensitivity reactions to aprotinin have been reported in adult cardiac surgical patients undergoing initial and re-exposure to the medication. This study describes the incidence and impact of aprotinin hypersensitivity reactions in children undergoing cardiothoracic surgery., Methods and Results: In this retrospective review of our entire experience with aprotinin (n=865), 681 first exposures, 150 second exposures, and 34 third or higher exposures were examined. Reactions were classified as mild (generalized cutaneous erythema, Type A) or severe (unexplained cardiopulmonary instability after aprotinin exposure, Type B). Records of patients sustaining a reaction were reviewed to assess the impact of the reaction on outcome and to survey reaction management strategies. Reactions occurred in 7 of 681 first exposures (1.0%), of which 2 were Type A and 5 were Type B. In second exposures, there were reactions in 2 of 150 (1.3%), of which both were Type B. In 34 third or higher exposures, there was only 1 reaction (2.9%), which was Type B. Reactions were no more likely on second, third, or higher exposure than on initial exposure. Skin testing had a negative predictive value of 98.9% and a positive predictive value of 20%. Anti-aprotinin IgE was undetectable in 7 of 8 reactor cases tested. No adverse sequelae were attributed to aprotinin reaction., Conclusions: The risk of hypersensitivity reactions to aprotinin is low in children undergoing cardiothoracic surgery, even with multiple exposures to the medication. Reactions are more likely with re-exposure, and risk increases with multiple exposures. Neither skin testing nor assays for IgE identified reactors.

Background: Aprotinin, a serine proteinase inhibitor, reduces bleeding during cardiac surgery. As aprotinin is derived from bovine lung, it has antigenic properties. This investigation examined the incidence of anaphylactic reactions in patients reexposed to aprotinin and the relation to preformed antiaprotinin immunoglobulin (Ig)G and IgE antibodies., Methods: This prospective observational study conducted at five centers in Germany evaluated patients undergoing repeat cardiac surgery reexposed to aprotinin between 1995 and 1996. Antiaprotinin IgG and IgE antibody measurements, using a noncommercial enzyme-linked immunosorbent assay and an immunofluorescence assay, respectively, were performed preoperatively and postoperatively. An anaphylactic reaction was defined as major changes from baseline within 10 min of aprotinin administration of systolic pressure 20% or greater, heart rate 20% or greater, inspiratory pressure greater than 5 cm H2O, or a skin reaction., Results: In 121 cases (71 adults, 46 children), a mean aprotinin reexposure interval of 1,654 days (range, 16-7,136 days) was observed. Preoperative antiaprotinin IgG (optical density ratio > 3) and IgE antibodies (radioallergosorbent test [RAST] score < 3) were detected in 18 and 9 patients, respectively. High concentrations of each (IgG, optical density ratio > 10; IgE, RAST score > or = 3) were detected in five patients. Three patients (2.5%; 95% confidence interval, 0.51-7.1%) experienced an anaphylactic reaction after aprotinin exposure, followed by full recovery; these patients had reexposure intervals less than 6 months (22, 25, and 25 days) and the highest preoperative IgG concentrations of all patients (P < 0.05). Assay sensitivity was 100%, as no anaphylactic reactions occurred in IgG-negative patients (95% confidence interval, 0.0-3.1%); assay specificity was 98%. Preoperative IgE measurements were quantifiable in two of three reactive patients and in three nonreacting patients., Conclusions: Quantitative detection of antiaprotinin IgE and IgG lacks specificity for predictive purposes; however, quantitation of antiaprotinin IgG may identify patients at risk for developing an anaphylactic reaction to aprotinin reexposure.

Unlabelled: Acute hypersensitivity reactions are serious complications of reexposure to aprotinin. Previous contact via infusions or fibrin tissue adhesives can induce specific antibodies. In this study, we aimed to elucidate the preoperative prevalence of aprotinin-specific antibodies in patients scheduled for cardiac operations. Sera of 520 consecutive cardiosurgical patients were collected preoperatively and screened retrospectively for aprotinin-specific IgG using a standard enzyme-linked immunosorbent assay (ELISA). Positive sera were analyzed also for aprotinin-specific IgA (ELISA) and IgE (fluorescence enzyme immunoassay). The histories of all patients were reviewed with focus on aprotinin preexposure. Of 520 patients, 22 (4%) had specific IgG. Only three of these had a documented aprotinin preexposure. Of 448 patients exposed to aprotinin intraoperatively, 15 had preformed specific antibodies. The only patient presenting with severe anaphylaxis was positive for both IgG and IgE, and had a recent IV preexposure in cardiovascular surgery. The presence of aprotinin-specific IgG alone seems not to induce adverse reactions on exposure. Exposure history alone is not sensitive enough to identify patients with aprotinin-specific antibodies., Implications: Anaphylaxis on IV reexposure to aprotinin is a medical emergency. The clinical significance of preformed aprotinin-specific IgG remains questionable, whereas preformed IgE was present in the only patient who suffered from severe anaphylaxis on reexposure to aprotinin. Preformed antibodies are not reliably predicted by exposure history.

Objective: Most commercially available fibrin sealants contain aprotinin in doses of 1500 kallikrein inactivator units per milliliter. They are used in many operative disciplines. An elevated risk of hypersensitivity reactions exists at reexposure to aprotinin. Our aim was to examine the immunogenic potency of aprotinin as a fibrin sealant content., Methods: We investigated 49 children with operatively treated congenital heart disease. All patients received aprotinin only topically as contained in fibrin sealant. Serum samples were drawn preoperatively, 1 week, 2 weeks, 6 weeks, and approximately 1 year after operation. They were analyzed for aprotinin-specific immunoglobulin G antibodies with a standard enzyme-linked immunosorbent assay and a fluorescence enzyme immunoassay for aprotinin-specific immunoglobulin E antibodies., Results: At 1 week, 2 weeks, 6 weeks, and 1 year, we found prevalences of 8% (2 of 26), 8% (2 of 24), 6% (3 of 49), and 0% for aprotinin-specific Immunoglobulin E, and for aprotinin-specific immunoglobulin G 8% (2 of 26), 17% (4 of 24), 39% (19 of 49), and 12% (5 of 41). The doses of aprotinin given did not differ significantly in antibody-negative and antibody-positive patients; no significant factors could predict the immune response., Conclusions: Our findings show the existence of a subgroup of patients who had aprotinin-specific antibodies develop after topical aprotinin application. Any use of aprotinin must be carefully documented. If aprotinin use is planned in patients who previously underwent a surgical procedure, preexposure to aprotinin in any form must be sought to avoid unexpected anaphylactic reactions. The necessity itself and alternatives for aprotinin as a stabilizing agent in fibrin sealants merit consideration.

We report a case of severe anaphylactic shock during a cardiac operation that occurred as a consequence of aprotinin readministration in the presence of preformed aprotinin-specific antibodies. Both immunoglobulin G (3 hours) and immunoglobulin E (5 minutes) antibody levels dropped early after the clinical event. Despite their possibly limited clinical significance, we still recommend the conductance of specific antibody screening tests before readministration of aprotinin.

High-dose aprotinin is now routinely used in cardiac surgery to reduce postoperative blood loss and transfusion requirements, although several cases of anaphylactic reactions to the proteinase inhibitor have been reported. As part of a multi-centre study to evaluate the immunological response to aprotinin after first exposure 61 cardiac surgical patients were treated with the Hammersmith regimen. Patients with previous aprotinin exposure were excluded from the study. To determine specific IgG and IgE antibodies blood samples were taken pre-operatively, within 3 to 4 weeks and 6 to 7 months after operation. Determinations were made by using Western Blot and ELISA methods. Fifty-six patients were followed up for a 6-month period, 26 (46.4%) of them developed IgG antibodies to aprotinin determined by Western Blot, whereas only 14 (26.8%) patients with IgG antibodies were found by the ELISA. IgE antibodies were not found in any of the patients. On hospital admission and 6 months post-operatively additional intradermal prick tests were performed. No clear-cut positive reaction to the skin test was found in any patient.