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Ann Thorac Surg 2007;84:1144-1150
© 2007 The Society of Thoracic Surgeons

Original Articles: Cardiovascular

Aprotinin and Anaphylaxis: Analysis of 12,403 Exposures to Aprotinin in Cardiac Surgery

Wulf Dietrich, MD, PhDa,b,*, Anna Ebell, MDc,b, Raimund Busley, MDc,b, Anna-Laure Boulesteix, PhDd,b

a Department of Anesthesiology, German Heart Center Munich, Germany
b Department of Cardiology, General Hospital Munich, Harlaching, Germany
c Department of Anesthesiology, Critical Care and Pain Therapy, Behandlungszentrum Vogtareuth, Germany
d Department of Medical Statistics and Epidemiology, Klinikum Rechts der Isar, Munich, Germany

Accepted for publication May 4, 2007.

* Address correspondence to Dr Dietrich, Winthistr. 4, Munich 80639, Germany (Email: wulf.dietrich{at}t-online.de).


Drs Dietrich and Busley disclose that they have a financial relationship with Bayer Corp.

 

   Abstract
Top
 Abstract
Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
 References
 
Background: Hypersensitivity reactions to the nonspecific proteinase inhibitor aprotinin may occur. The present study evaluates the incidence of hypersensitivity reactions to aprotinin.

Methods: Data were prospectively collected as part of the institution’s quality assurance program. The database was screened for anaphylactic reactions, especially those against aprotinin. The definition of an allergic reaction was predefined. A severe reaction was definded as hemodynamic instability of more than 10 minutes despite high dosages of vasopressors and inotropic medication.

Results: Of 13,315 cardiac operations, 12,403 were done with aprotinin, with 801 reexposures in 697 patients. Eleven reactions to aprotinin (11 of 11,602; 0.09%, 95% confidence interval: 0.05% to 0.16%) were recorded after primary exposure, of which none was severe, while 12 reactions (12 of 801; 1.5%; 95% confidence interval: 0.86% to 2.6%) occurred after reexposure, of which 5 were severe. All severe reactions were in patients reexposed to aprotinin within 6 months after previous exposure. There was no reaction observed in patients reexposed to aprotinin within 3 days after the last exposure (n = 42). The incidence of hypersensitivity reactions was 4.1%, 1.9%, and 0.4% in the less than 6 months, 6 to 12 months, and more than 12 months reexposure intervals, respectively.

Conclusions: The risk of hypersensitivity reactions is low after primary exposure to aprotinin. This risk after reexposure reaches a maximum between the fourth day and the 30th day after previous exposure and declines considerably after 6 months. Consequently, application of aprotinin carries a high risk between the fourth and the 30th day after previous exposure, and cannot be recommended for the first 6 months, but is justifiable in previously aprotinin-exposed patients with a high risk of bleeding after this interval.

Aprotinin is a small polybasic polypeptide indicated to reduce prophylactically the risk of bleeding and transfusion during cardiac surgery with cardiopulmonary bypass. At the full-dose regimen, aprotinin has robust blood-sparing [1] and possible anti-inflammatory properties [2]. The product has garnered widespread use in cardiac and other major surgeries [3, 4]. Although infrequent, hypersensitivity reactions to aprotinin, which is a protein derived from bovine lung, can occur [5–10]. Upon primary exposure to aprotinin, the rate of hypersensitivity reactions observed is less than 0.1% [5]. Upon reexposure, the incidence of hypersensitivity reactions was previously reported to be 2.8% in a cohort of 240 patients undergoing heart surgery [6]. A separate study reported a slightly lower rate of 1.6% after reexposure [10].

The frequency of hypersensitivity reactions diminishes with respect to time after exposure [6, 9]. In a study of 240 patients, the frequency of reactions in patients reexposed to aprotinin before versus after 6 months dropped significantly from 4.5% to 1.5% [6]. Similarly, in a literature-based analysis of hypersensitivity reactions to aprotinin, the number of reactions dropped beyond the 3 month reexposure time point [9]. Hypersensitivity reactions to aprotinin were associated with the presence and with the concentration of IgG antibodies [8].

Recently, the efficacy and side effects of aprotinin in cardiac surgery have been disputed [11–13]. Hypersensitivity reactions were also of interest in this context [14]. The labeling for aprotinin regarding anaphylactic reactions was updated by the Food and Drug Administration in December 2006 (http://www.fda.gov/cder/drug/infopage/aprotinin/default.htm). Because patients with previous heart surgery are at greater risk of bleeding, the use of aprotinin especially in these patients, who might have been exposed to aprotinin during the first operation, may be particularly beneficial. Therefore, it is important to investigate the incidence of hypersensitivity reactions to aprotinin in patients with previous exposure to this drug.

We previously reported the incidence of hypersensitivity reactions to aprotinin in our patients between 1988 and 1995 [6, 15]. We now continued this evaluation with a new database in our patient population between 1995 and 2003. The following retrospective analysis was performed to characterize anaphylactic reactions to aprotinin and, specifically, to find out whether and when the drug can be used again after primary exposure.


   Material and Methods
Top
 Abstract
 Introduction
 Material and Methods
Results
 Comment
 Acknowledgments
 References
 
Study Design
All patients undergoing cardiac surgeries performed between 1995 and 2003 at the German Heart Center Munich were retroprospectively evaluated for aprotinin use and hypersensitivity reactions. Data used in this analysis were retrieved from the institutional cardiovascular anesthesia database that includes data collected as part of the national quality assurance project of cardiac anesthesia [16] in Germany. The database was revised 1995 with special focus on hypersensitivity reactions and collects prospectively a comprehensive list of 238 prespecified items in all consecutive patients, including demographic, clinical, and other outcome data. Because our center is involved in studies about the use and mode of action of aprotinin in cardiac surgery over a long period [6], a special interest in data collection is put on aprotinin-related items including possible hypersensitivity reactions. In detail, besides demographic data, bleeding and transfusion-related items, aprotinin dosage, interval since previous exposures to aprotinin, the type of hypersensitivity reaction or suspected reaction, and management of the reaction were recorded. Data pertaining to hypersensitivity reactions to aprotinin from a small subset of these records (n = 76) have been previously analyzed and published [8]. Two of the previously described reacting patients are included in the present study. The evaluation was subject to review and approval by the Ethics Committee of the medical faculty of the Technical University Munich. All of the patients had previously granted written permission for use of their medical records for research purposes.

Aprotinin was purchased from a single manufacturer (Trasylol; Bayer GmbH, Leverkusen, Germany). The exposure rate and not the patients were counted in this study; thus, patients with more than one exposure were reported repeatedly. Each patient received an aprotinin test dose of 1 x 104 KIU at least 10 minutes before the administration of the first aprotinin bolus. If the test dose was tolerated without adverse reaction, treatment of adult patients was initiated after sternotomy with a loading dose of 2 x 106 KIU administered over 15 minutes, followed by a continuous infusion of 5 x 105 KIU/h (50 mL/h). Additionally, the oxygenator was primed with 2 x 106 KIU aprotinin. In pediatric patients—arbitrarily defined in this study as patients aged less than 18 years with congenital heart disease—aprotinin dose was partially based on weight [17]. After the test dose, the first aprotinin bolus consisted of 3 x 104 KIU/kg, and the oxygenator was primed with the same dosage but at least 5 x 105 KIU. A continuous infusion of aprotinin was not used in pediatric patients.

Histamine H1 and H2 receptor antagonists were administered prophylactically at the induction of anesthesia in all patients previously exposed to aprotinin. Treatment of adult patients included either dimetindine 0.1 mg/kg or clemastine 0.03 mg/kg together with cimetidine 5.0 mg/kg, ranitidine 2.0 mg/kg, or famotidine 20 mg. Additional corticosteroid treatment was administered at the discretion of the attending anesthesiologist. Pediatric patients received a weight-adjusted reduced dosage.

Anesthetic and cardiopulmonary bypass (CPB) techniques employed were according to the practice of our institution described elsewhere [18].

The occurrence of an allergic reaction was assumed if at least one of the following symptoms was present in the context of aprotinin administration [19]: (1) systolic blood pressure decrease of greater than 20%; (2) heart rate increase greater than 20% from baseline; (3) inspiratory airway pressure increase greater than 5 cm H2O; and (4) skin reaction. The nature of the hypersensitivity reaction was determined at the time of reaction based on evaluation by the attending anesthesiologist. Association with aprotinin was assumed if one of the symptoms occurred after aprotinin injection within 15 minutes. The reaction was judged as severe (hemodynamic instability despite high dosages of vasopressors and inotropic medication), moderate (restoration of hemodynamics within 10 minutes after vasopressor therapy), or questionable (if the association of the reaction with aprotinin was not clear or the patient recovered without pharmacological intervention) based on the clinical symptoms. The charts of all patients with a reported anaphylactic reaction were rechecked independently by two of the authors (W.D., A.E.). In case of doubt, the original judgment of the attending anesthesiologist was maintained.

The primary outcome measure was the incidence of allergic/anaphylactic reactions and their relation to aprotinin treatment.

Statistical Analyses
Continuous variables are presented as mean ± SD or median, or both, followed by first and third quartiles. Binary variables are presented as rates with 95% confidence intervals (CI). Fisher’s exact test was used to test the equality of rates. Association between a binary outcome and a continuous predictor was evaluated based on binary logistic regression. These statistical analyses were performed using SPSS for Windows, version 14 (SPSS GmbH, Munich, Germany). A result was considered significant at p less than 0.05.


   Results
Top
 Abstract
 Introduction
 Material and Methods
 Results
Comment
 Acknowledgments
 References
 
Surgical procedures were performed in 13,315 patients, of whom 3,270 were pediatric patients. There were 2,561 patients (pediatric, 1,296; adult, 1,265) with previous sternotomy. Pediatric and adult patients were on average 3.5 ± 5.4 years of age (median, 1 [0 to 6]) and 63.5 ± 16.9 years of age (median, 66 [57 to 73]), respectively. Coronary artery bypass surgery and surgery for congenital heart disease were the most frequently performed procedures (Table 1). Duration of operation was 239 ± 103 and 242 ± 81 minutes, and time on cardiopulmonary bypass was 102 ± 61 and 103 ± 44 minutes in pediatric and adult patients, respectively.


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  		Table 1 Aprotinin Exposure During Cardiac Surgery
 
Ninety-three percent of the operations (n = 12,403) were performed with the use of aprotinin (Fig 1). Mean aprotinin dosage was 1.47 x 106 ± 1.34 KIU (median, 1 [1 to 2] KIU) in pediatric patients (n = 2,769) and 5.40 x 106 ± 0.98 KIU (median, 5 [5–6] KIU) in adult patients (n = 9,634). Reexposure to aprotinin occurred 801 times (6.5%, 95% CI: 6.0% to 6.9%) in 697 patients (Table 1). Of these 697 patients, 605 patients had one reexposure to aprotinin, 83 were twice exposed, 6 patients were three times exposed, and 3 patients received aprotinin during four operations.


Figure 1
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  		Fig 1. Consolidated Standards of Reporting Trials (CONSORT) diagram of patient enrollment. The diagram shows the number of patients with primary exposure and the number of reexposures to aprotinin. Patients with reexposure are divided into patients with reexposure to aprotinin within 6 months and after 6 months. Of note, all severe reactions to aprotinin occurred among patients with reexposure within 6 months after the previous treatment with the drug.

 
Twenty-three patients (0.19%, 95% CI: 0.12% to 0.29%; 23 of 12,403 exposures) had a hypersensitivity reaction to aprotinin and another 23 patients (0.19%, 95% CI: 0.12% to 0.29%; 23 of 12,403 exposures) had one deemed unrelated to aprotinin. Thus, overall hypersensitivity reactions occurred in 0.4% (95% CI: 0.3% to 0.5%) of all operations. Other than aprotinin, agents thought to elicit hypersensitivity reactions included protamine (n = 5), antibiotics (n = 5), and colloid solution (n = 1); in 12 patients, the trigger agent could not be identified. In these patients, a reaction to aprotinin was ruled out by timing of the reaction.

Among patients who had been exposed to aprotinin, 11 hypersensitivity reactions to aprotinin were noticed after primary exposure (n = 11 of 11,602 [0.09%], 95% CI: 0.05% to 0.16%); none was severe, 5 were moderate, and 6 were questionable (Table 2). In contrast, after reexposure, 12 reactions to aprotinin occurred (12 of 801 [1.5%], 95% CI: 0.86% to 2.6%). Of these 12 reactions, 5 were severe, 5 were moderate, and 2 were questionable. Nine of 12 reactions were recorded after the injection of the test dose, 4 of 5 severe reactions happened after the test dose, whereas the reaction in the fifth patient was recorded just after start of the continuous infusion. One of the 5 patients with severe reactions—a reaction to the test dose—died postoperatively (patient 2 in Fig 2). This patient had a pulmonary atresia and was operated on because a residual ventricular septal defect and a stenotic allograft 22 days after a right ventricle to pulmonary artery allograft implantation combined with aortic valve replacement. The operation was technically demanding, and the CPB time was 290 minutes. Despite extremely high dosages of epinephrine and vasopressors, the perfusion pressure during CPB was remarkably low. The patient died of multiorgan failure on the first postoperative day. In patients with primary exposure, in 6 of 11 patients, a reaction to the test dose was suspected, and the patients were not treated with the full dose of aprotinin. The proportion of reacting patients was significantly higher after reexposure than after primary exposure (p < 0.001).


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  		Table 2 Hypersensitivity Reactions to Aprotinin in Reexposures to Aprotinin (n = 12) and in Primary Exposures (n = 11)
 

Figure 2
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  		Fig 2. Time to reexposure and severity of hypersensitivity reaction (circles = severe; squares = moderate; diamonds = questionable). This figure shows the patients with reexposure to aprotinin and a hypersensitivity reaction ordered by the time since the last exposure to the drug. Severe reactions occurred only within 6 months after exposure to the drug, especially within the first 4 weeks after the last aprotinin treatment. The definition of severity is given in the text.

 
The rate and severity of hypersensitivity reactions due to reexposure decreased with the time interval since previous exposure. Eight of the 194 patients (4.1%, 95% CI: 2.1% to 7.9%) who were reexposed to aprotinin within 6 months of the primary exposure had a hypersensitivity reaction, 2 of 102 patients (1.9%, 95% CI: 0.5% to 6.9%) between 6 and 12 months of reexposure had a hypersensitivity reaction, whereas only 2 of the 505 patients (0.4%, 95% CI: 0.01% to 1.4%) who were reexposed after more than 1 year were reported to have a reaction (Table 3). None of these reactions was severe. If patients exposed within three days after the operation (n = 42) were not counted, because it is unlikely to develop antibodies against aprotinin within this time frame, the incidence of hypersensitivity reactions within the first 6 months was 5.3% (8 of 152 exposures; 95% CI: 2.7% to 10.0%). Between the fourth and the 30th day, the risk was 7.4% (4 of 54 exposures; 95% CI: 2.4% to 18.8%). In univariate binary logistic regression, time since previous exposure was a significant predictor of hypersensity reaction (p = 0.022).


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  		Table 3 Hypersensitivity Reactions to Aprotinin After Reexposure in Relation to the Exposure Interval
 
All five severe reactions during reexposure occurred in the "less than 6 months" time frame—the majority within 30 days after the previous exposure (Table 3). One patient of the five with severe reactions had a re-reexposure to aprotinin with no reaction to the second exposure but a severe reaction to the third exposure. Interestingly, this patient had two additional operations after the reaction: 3 months after the reaction surgery was performed without aprotinin, but 6 years later, aprotinin (4 x 106 KIU) was unintentionally given without any adverse reaction. Severity of reaction and time to reexposure were plotted for all 12 patients who experienced hypersensitivity reactions to aprotinin (Fig 2).

When reactions were broken down by date of surgery, all 5 severe reactions took place between 1995 and 1998; later on, no severe reaction was reported.


   Comment
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
Acknowledgments
 References
 
This study included 12,403 operations, the largest cohort exposed to aprotinin and evaluated for hypersensitivity reactions to date (Table 4). The incidence of hypersensitivity reactions to aprotinin reexposure observed (1.5%; 12 of 801 exposures) was consistent with data from other studies, which estimate a 1.2% to 2.8% reaction rate [6, 8–10, 15]. Jaquiss and colleagues [10] found a 1.6% incidence rate in a data set (n = 184) that included patients with second and third exposures. In contrast to our results, these authors did not demonstrate an association between the time interval since the previous exposure and the incidence of anaphylactic reactions. However, the number of reacting patients was small, and the number of patients reexposed within a short time interval was not reported by the authors. In other studies, slightly higher incidences after reexposure (2.5% and 2.8%) have been reported [6, 8, 9].


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  		Table 4 Distribution of Aprotinin Exposures Among Acquired and Congenital Heart Disease Patients
 
The decrease in incidence and severity of reactions over time from previous exposure is also consistent with previous data. The incidence of 4.1% (8 of 194 exposures) noted within 6 months of initial exposure dropped to 2.0% (2 of 102 exposures) between 6 and 12 months, and was 0.4% (2 of 505 exposures) beyond the 12-month time point. Similar trends have been noted in the other studies [6, 8, 9]. These data are also consistent with the reported drop over time in the number of patients carrying aprotinin antibodies [7]. However, patients with an immediate reexposure within the first 3 days after the primary operation are not likely to develop antibodies within this time and should, therefore, not be counted. This is an important observation, as early reoperation frequently occurs and is associated with high risk of bleeding; however, according to the label, aprotinin is contraindicated in these patients. The incidence of hypersensitivity reactions between 4 and 30 days after exposure was 7.4% (4 of 54 exposures), indicating that this is the most risky period.

Interestingly, 1 of the 5 reacting patients had a re-reexposure and reacted after the third exposure. In this patient, a booster effect with an intense development of antibodies to aprotinin may have occurred during the second exposure. This patient was reexposed again to aprotinin after 6 years without reaction. That indicates the disappearance of antibodies over time, which is also reported for other types of antibodies [20].

Virtually all severe reactions happened immediately after the application of the test dose, raising the question of the usefulness of the test dose. The advantage of the test dose is that it concentrates the attention of the anesthesiologist to possible reactions and reduces the total antigenic load if only a small amount of the drug is infused. But it does not avoid a severe reaction. However, the application of a lower than the recommended amount of the test dose may be considered.

Data revealed that no severe reactions occurred after 1998. That could be explained by the improved screening of patients at risk for aprotinin reactions, reexposure to aprotinin was done more carefully, and patients with a short period since the previous exposure were not treated with aprotinin.

The incidence of hypersensitivity reactions in patients who had not been previously exposed to aprotinin, according to their records, is difficult to interpret. Often, these reactions were "questionable" and reported after the injection of the test dose. Because the full dose of aprotinin was not applied in these patients and the reactions were only mild and transient, it remains questionable whether these incidences were hypersensitivity reactions or just a precaution of the anesthesiologist. Otherwise, the reactions noted may have, in part, been due to hidden exposures to aprotinin in products such as fibrin glues [21]. The study design may have allowed for unknown exposures to aprotinin. Consistent with this hypothesis, 10 of the 11 primary reactions occurred in adults, who have had a longer life span during which a hidden exposure may have occurred. However, an anaphylactic reaction to aprotinin in a patient without obvious pretreatment with aprotinin has been described recently [22].

Under clinical conditions, it may be difficult to identify hypersensitivity reactions. The patients are totally draped so the skin is not visible, and hemodynamic changes may be caused by surgical manipulation of the heart. However, severe reactions can easily be identified: the patient is totally vasoplegic, and obtaining and maintaining adequate perfusion pressure during CPB are extremely difficult despite exorbitant dosages of epinephrine and vasopressors.

Because hypersensitivity reactions are hard to anticipate and patients may not know if they have been previously exposed to aprotinin, detection of aprotinin-specific antibodies may help predict reaction risks [21, 23]. In a more recent study, antiaprotinin immunoglobulin (Ig) G, but not IgE, was found to predict hypersensitivity reactions in the 3 of 121 patients who experienced an immediate hypersensitivity reaction to aprotinin reexposure. These patients were reexposed to aprotinin after 22 or 25 days and had the highest preoperative IgG concentrations recorded in the entire patient group. In 15% (18 of 121) of the reexposed patients, IgG antibodies were detectable already preoperatively [8]. But not all patients with positive antibody results reacted to aprotinin. Thus, this study demonstrated that not the existence of IgG antibodies per se was predictive for a reaction, but the height of the titer as measured by the optical density of the test system was crucial for a reaction.

Although the present manuscript focuses on hypersensitivity reactions to aprotinin during cardiac surgery, these data also show that anaphylactic reactions to other agents used during surgery exist [24]. Reactions to other agents occurred as often as did those to aprotinin, but were less severe. We found reactions to protamine (n = 5), antibiotics (n = 5), hydroxyethylstarch (n = 1), and 12 reactions for which the trigger agent could not be identified. Other agents generating anaphylaxis perioperatively include, but are not limited to, latex, gelatine, blood, hirudin, dextran, and pentoxifylline [24–27].

Some surgical procedures are related to increased risk of anaphylactic reactions—not because of the nature of these operations but because of the propability of a second intervention shortly after the first operation. These operations include the correction of congenital heart defects—revision of a shunt, two-stage repair of a hypoplastic left heart [28]—failed mitral valve repair [29], and assist device implantation followed by heart transplantation [30]. The majority of reported cases of anaphylaxis to aprotinin include these operations.

Limitations of the Study
Several limitations of our analysis deserve comment. This is a retrospective analysis of a single institution database. The diagnosis of hypersensitivity reaction was solely based on clinical judgment and, in almost all cases, not confirmed by antibody testing. The identification of moderate reactions may be difficult. The incidence of moderate reactions may have been overestimated in this study, because hemodynamic reactions at the time of aprotinin infusion may be provoked by manipulation of the heart, cannulation of the aorta or the right atrium, or bleeding, and not by a hypersensitivity reaction to aprotinin. On the other hand, the incidence of reactions may have been underestimated because the association of a reaction to aprotinin can easily be overlooked in case of a mild or moderate reaction. But a severe reaction, which is clinically important, is a dramatic event and cannot be ignored. Fortunately, the incidence of hypersensitivity reactions is low, and subsequently, the confidence intervals of our incidence numbers are high, and our recommended safe time intervals to reexposure are rough estimates. Finally, the influence, if any, of treatment with H1 and H2 blockers on the severity of the reaction cannot be estimated from the current data.

Conclusions
In patients reexposed to aprotinin, the highest risk of a hypersensitivity reaction occurred within the first 6 months after exposure to aprotinin (4.1%). Within this 6-month period, patients should not be reexposed to aprotinin. Immediate postoperative reexposure is possible, but reexposure between 4 and 30 days after primary exposure has an incidence of 7.4% of a hypersensitivity reaction and, therefore, aprotinin should not be used during this period. As an alternative to aprotinin, tranexamicacid or other lysine analogues may be used in this period [31]. Beyond 6 months, hypersensitivity risk dropped to 0.8%, suggesting that aprotinin can be given if the risk of bleeding is high and precautions are taken. Recently, the FDA recommended a time window of 12 months after the previous exposure (available at: http://www.fda.gov/cder/drug/infopage/aprotinin/default.htm). In the case of primary exposures, the risk of hypersensitivity is low and comparable with that of protamine, but physicians should be aware that patients may have been exposed to aprotinin through fibrin glue or during other types of operations.


   Acknowledgments
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
References
 
This work was funded by the medical faculty of the Technical University Munich. We thank Helga Seggebrock, German Heart Center Munich, for assistance in data collection and review of the patients’ records.


   References
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
 References
 

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