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Ann Thorac Surg 1996;61:1288-1289
© 1996 The Society of Thoracic Surgeons
Departments of Cardiac Surgery and Anesthesia, University Hospital, IRCCS Policlinico S Matteo, I-27100 Pavia,Italy
To the Editor:
The recent article by Goldstein and colleagues [1] is an excellent review of a multicentric experience of left ventricular assist device implantation, focused on the use of aprotinin to facilitate hemostasis. We agree with Goldstein and colleagues that limiting the requirement of packed red cells and blood products during the insertion of a mechanical assist device for staged heart transplantation is of utmost importance to preserve pulmonary function and prevent right heart failure. The drug seems to be essentially safe, as demonstrated by its relatively long-standing extensive use in cardiac surgery [2]. Among the adverse events listed in the article, a case of hypotension at the time of transplantation is reported but the incidence of anaphylaxis was zero. However, in the discussion Dr Loebe refers to a patient who died as a consequence of a severe allergic reaction to aprotinin. Because aprotinin is a polypeptide derived from bovine organs, there is always the possibility of a sensitization to the agent with an anaphylactic reaction after a second administration; the incidence of this in the literature is reported to be between 0.22% and 10% of cases [3, 4].
In our institution we routinely use aprotinin in general cardiac operations and in thoracic organ transplantation as well as during implantation of mechanical assist devices, according to a modified Royston protocol (2,000,000 KIU [280 mg] before cardiopulmonary bypass, 2,000,000 KIU [280 mg] in the priming and 600,000 KIU [84 mg] in continuous perfusion for 6 hours after cardiopulmonary bypass).
Even if in our experience the introduction of aprotinin in clinical practice was of tremendous benefit, an anaphylactic reaction with fatal consequences that occurred at the moment of transplantation in a patient supported with a left ventricular assist device prompted us to reexamine our protocols and to be more cautious. A 56-year-old patient with dilated cardiomyopathy underwent LVAD implantation (Novacor N100P; Baxter Healthcare Corp, Oakland, CA) because of refractory cardiac failure despite intraaortic counterpulsation. During the operation aprotinin was administered according to our standard protocol. The immediate postoperative course was complicated by dynamic subocclusion of the colon, hemorragic gastritis, and respiratory insufficiency, which required prolonged ventilation. On day 30 he underwent mediastinal debridement and sternal reapproximation for complete sternal dehiscence complicated by local and systemic enterococcal infection. Because of diffuse bleeding in the surgical field 600,000 KIU (84 mg) of aprotinin was administered; shortly thereafter bronchospasm developed, which was immediately treated with injection of solbutamol and hydrocortisone. An allergic reaction to aprotinin was suspected, and a thorough laboratory evaluation and immunologic profile was carried out. Total immunoglobulin E level was 271 KU/L (normal value, <250 KU/L). The concentration of tryptase, a mediator released by mast cells, normally undetectable, was 8 U/L, and this is the only test that could probably support the thesis of an allergic reaction to aprotinin. The anti-aprotinin immunoglobulin E antibody radioallergoadsorbent test was not performed because of the unavailability of the proper kit.
The patient recovered rapidly and, fully rehabilitated, was allowed short out-of-hospital stays. Elective heart transplantation was performed 77 days after left ventricular assist device implantation and 47 days after the second exposure to aprotinin. The routine test dose of 10,000 KIU (1.4 mg) of aprotinin administered before CPB caused immediate hypotension with loss of peripheral vascular tone, unresponsive to pharmacologic treatment (epinephrine and norepinephrine up to 0.5 µg • kg-1 • min-1) and high-flow cardiopulmonary bypass. The operation was completed, but the patient died on day 15 of multiorgan failure directly related to the perioperative shock.
This dramatic experience raises some considerations regarding the appropriate use of this very effective drug in staged cardiac transplantation, where two consecutive major operations are necessary: (1) Because any drug or blood product can cause anaphylaxis in the case of repeated exposure to aprotinin, it is advisable to follow the recommendations proposed by Levy [4], first performing the prick test, then the intradermal test followed by an intravenous test dose. (2) Due to the risk of repeated administration, even if the extension of the potentially bleeding surface and the stiffness of the adhesions can complicate hemostasis at the removal of the device, we prefer to reserve the use of aprotinin to the implantation phase, in which limited bleeding can significantly contribute to preserve the pulmonary function and right heart hemodynamics. (3) Because some biological glues contain aprotinin, one must be aware of the possibility of concealed causes of sensitization.
References
Division of Cardiothoracic Surgery, Columbia-Presbyterian Medical Center, Milstein Hospital, Suite 7–435, 177 Ft Washington Ave, New York, Ny 10032
To the Editor:
I have reviewed the letter by Martinelli and associates regarding the risk of anaphylactic reactions to repeat aprotinin use. In the case reported, the anaphylactic reaction causing death occurred after the third administration of the drug in a short period. Because aprotinin is an animal protein, the incidence of hypersensitivity reactions would be expected to increase with each reexposure. Because hypersensitivity-type reactions can range from mild symptoms like pruritis, dyspnea, and tachycardia to sometimes fatal anaphylactic shock, the potential ramifications should not be underestimated.
My colleagues and I routinely use aprotinin both at the time of long-term left ventricular assist device insertion and at the time of heart transplantation several months later. Of the 33 patients undergoing both procedures (device insertion and subsequent heart transplantation) we have had one episode of anaphylactic shock resulting from the readministration of aprotinin. In this patient, we rapidly exposed and cannulated the femoral artery and vein and achieved cardiopulmonary bypass with excellent flows although our systemic pressures remained at approximately 20 mm Hg. After stopping the aprotinin administration and administering appropriate high-level vasoconstricting agents, we were able to achieve a reasonable blood pressure within 10 minutes, and the patient subsequently survived the transplantation and was neurologically intact. Since this episode, we have routinely exposed the aorta or femoral artery before administering the repeat dose of aprotinin. We recognize that we lose the antiinflammatory and antifibrinolytic benefits of the drug during the initial skin incision and sternotomy; however, this provides us an extra level of safety in the event of an unexpected anaphylactic reaction.
With this policy, we have been able to administer the drug with confidence. In the event of circulatory collapse, we would be able to rapidly achieve cardiopulmonary bypass and resuscitate the patient. In addition, we obtain the benefits of less bleeding and less blood product requirements with less right-sided circulatory failure. Surgeons should be aware that although the incidence of anaphylaxis is extremely small at the time of initial aprotinin administration, the incidence of anaphylaxis during readministration may be as high as 5% [1]. The technique we offer will provide a buffer in this group of patients.
Reference
This article has been cited by other articles:
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  W. Dietrich, A. Ebell, R. Busley, and A.-L. Boulesteix Aprotinin and Anaphylaxis: Analysis of 12,403 Exposures to Aprotinin in Cardiac Surgery Ann. Thorac. Surg., October 1, 2007; 84(4): 1144 - 1150. [Abstract] [Full Text] [PDF]
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W. Beierlein, A. M. Scheule, W. Dietrich, and G. Ziemer Forty Years of Clinical Aprotinin Use: A Review of 124 Hypersensitivity Reactions Ann. Thorac. Surg., February 1, 2005; 79(2): 741 - 748. [Abstract] [Full Text] [PDF]
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