Wolfram Beierlein

Fibrin sealant, aprotinin, and immune response in children undergoing operations for congenital heart disease

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.

Aprotinin in fibrin tissue adhesives induces specific antibody response and increases antibody response of high-dose intravenous application☆☆☆★

BACKGROUND In cardiac operations, aprotinin therapy is used either locally as a component of commercially available fibrin tissue adhesives, intravenously, or combined. Our aim was to examine the formation of aprotinin-specific antibodies with regard to the application mode. METHODS Sera of 150 patients who had undergone cardiac operations and were receiving aprotinin therapy for the first time were sampled before the operation and at medians of 3.5 and 13.3 months after the operation. Aprotinin-specific IgG including all subgroups and aprotinin-specific IgE were analyzed. Aprotinin was given locally (as contained in fibrin sealant; n = 45; median dose, 6000 KIU), intravenously (n = 46; 2.000 x 10(6) KIU), and combined (n = 59; 2.012 x 10(6) KIU). RESULTS At 3.5 months, the prevalence of aprotinin-specific IgG antibodies was 33% (15/45 patients) after local, 28% (13/46 patients) after intravenous, and 69% (41/59 patients) after combined exposure (P =.0001). At 13.3 months, the prevalence of aprotinin-specific IgG antibodies was 10% (4/41 patients) after local, 31% (13/42 patients) after intravenous, and 49% (28/57 patients) after combined exposure. Total aprotinin dose was similar in patients who were antibody positive and negative. Before the operation, no aprotinin-specific antibodies were detected. Aprotinin-specific IgE were not found after the operation. CONCLUSION Local aprotinin contact induces a specific immune response and reinforces that of intravenous exposure. The antibody spectrum is identical to the immune response induced by intravenous exposure. Any exposure should be documented. For use in cardiac operations as a hemostyptic, the necessity itself and alternatives for aprotinin as a stabilizing agent merit consideration.

Sodium–hydrogen inhibitor cariporide (HOE 642) improves in situ protection of hearts from non–heart-beating donors

BACKGROUND Reperfusion injury is a vital problem in non-heart-beating donor (NHBD) organs. The sodium-hydrogen inhibitor cariporide is thought to improve cellular integrity after ischemia and reperfusion. Recently, we demonstrated the possibility of preserving hearts with in situ perfusion after circulatory death. The purpose of this study was to determine whether cariporide improves in situ heart protection. METHODS We studied 20 pigs (18 +/- 2 kg). Hearts in the conventional group (CON, n = 6) underwent cardioplegic arrest with University of Wisconsin solution and then were explanted and stored for 150 minutes on ice. In the other groups, a catheter was placed in each ascending aorta and right atrium. After disconnecting the ventilator, hypoxia caused circulatory arrest within 7 +/- 2 minutes. The aorta was endoclamped, and continuous in situ perfusion of the aortic root was maintained for 60 minutes with University of Wisconsin solution (UW, n = 7) or with UW solution and cariporide (CAR, n = 7). After explantation, the hearts were stored on ice for 90 minutes. In all groups, hearts were reperfused with homologous, whole pig blood in an isolated working heart model for 45 minutes. We monitored stroke-work index on-line, intermittently measured troponin I and malondialdehyde, and compared light microscopic examinations among the groups. RESULTS Stroke-work index was higher in the CAR group compared with the UW group during the last 20 minutes of reperfusion (10(3)dynes x cm x beats(-1)x gm(-1), 6.6 +/- 1.4 vs 4.5 +/- 2.0, p < 0.05), troponin I was lower in the CAR group compared with the UW group (161 +/- 32 ng/ml vs 277 +/- 35 ng/ml, p < 0.05). Results of malondialdehyde and light microscopic examinations were slightly better in the CAR group, without reaching statistical significance. CONCLUSION Cariporide as an additive to UW solution improves functional recovery and decreases myocardial damage in hearts from NHBDs protected with an in situ perfusion technique.

Glycoprotein IIb/IIIa inhibition reduces prothrombotic events under conditions of deep hypothermic circulatory arrest

Deep Hypothermic Circulatory Arrest (DHCA) is employed during thoracic aortic and congenital heart surgery, and can induce postoperative neurological damage probably caused by microthrombembolism. Hypothermia has been reported to induce platelet activation and aggregation. The platelet activation marker P-selectin mediates binding of platelets to leukocytes. Tirofiban and eptifibatide, short-acting inhibitors of the platelet fibrinogen receptor GP IIb/IIIa, have recently been shown to protect platelet function without increasing bleeding during heart surgery using cardiopulmonary bypass. The aim of this study was to investigate the effect of tirofiban and eptifibatide on platelets and platelet-leukocyte interaction under DHCA conditions in vitro. Platelet aggregation, binding of the GP IIb/IIIa activation specific antibody PAC-1, P-selectin expression as well as monocyte and granulocyte content of aggregates were investigated in unstimulated and ADP-stimulated samples using flow cytometry. Tirofiban and eptifibatide inhibited massive platelet aggregation and PAC-1 binding which were induced by DHCA conditions. P-selectin expression was inhibited by tirofiban but increased by eptifibatide at hypothermia. Platelet-bound leukocytes were present in all samples. Eptifibatide increased granulocyte content of aggregates at hypothermia in ADP-stimulated samples. We conclude that under conditions of DHCA both tirofiban and eptifibatide inhibit platelet aggregation but have different effects on platelet P-selectin expression and platelet-leukocyte interaction. Application of a short-acting and non-activating GP IIb/IIIa inhibitor should be considered during DHCA in vivo to prevent occlusion of the microvasculature and subsequent organ damage.

Extracorporeal circulation without external clamping and cannulation of the aorta: transventricular placement of a new multifunctional aortic cannula.

BACKGROUND Stroke is a devastating outcome of coronary artery bypass grafting (CABG). An atherosclerotic ascending aorta is a major risk factor for plaque detachment during cannulation and external clamping in patients undergoing CABG while on extracorporeal circulation (ECC). To avoid external cannulation and clamping we developed and tested a new multifunctional cannula in a pig model. METHODS The cannula has a double-balloon endoclamping function and is placed via the apex of the left ventricle through the aortic valve in the ascending aorta. It has 2 integrated lines for cardioplegic solution and for venting the left ventricle. In this animal model, a single balloon cannula was used because of the short ascending aorta in pigs. RESULTS The cannula was placed smoothly and reproducibly with a guide-wire technique. The cardioplegic solution was administered via aortic root perfusion. Weaning from ECC was uneventful, and macroscopic examination did not reveal any damage to the aortic valve. CONCLUSIONS This cannula could be used in patients with a severe atherosclerotic ascending aorta. The risk of plaque detachment and stroke during ECC might be reduced.