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Ann Thorac Surg 1999;67:173-176
© 1999 The Society of Thoracic Surgeons

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Original Articles

Reduced inotropic support after aprotinin therapy during pediatric cardiac operations

^a Department of Pediatric Cardiology, University of Mainz, Mainz, Germany
^b Department of Cardiovascular Surgery, University of Mainz, Mainz, Germany
^c Department of Anesthesiology, University of Mainz, Mainz, Germany

Accepted for publication June 15, 1998.

Address reprint requests to Dr Wippermann, Pediatric Cardiology, University Children’s Hospital, Langenbeckstr. 1, 55101 Mainz, Germany
e-mail: C.-F.Wippermann{at}t-online.de

	Abstract

Top Abstract Introduction Material and methods Results Comment References

 
Background. Several reports indicate that aprotinin treatment before and during cardiopulmonary bypass (CPB) might have a protective effect on the myocardium. We evaluated the hemodynamic effects of perioperative aprotinin treatment.

Methods. We conducted a randomized, double-blind, placebo-controlled trial in 34 infants (mean age, 2.5 years) who had cardiac operations. Half of the patients received high-dose aprotinin therapy. There were no significant differences between the aprotinin and placebo groups with respect to age, weight, sex, aortic cross-clamp time, and CPB time. The following data were recorded at arrival in the intensive care unit 6, 12, 24, and 48 hours after termination of CPB: heart rate, blood pressure, left atrial pressure, central-peripheral temperature difference, arterial-central venous oxygen saturation difference, urine output, serum creatinine, lactate and neutrophil elastase levels, the Doppler echocardiographic factors shortening fraction and preejection period/left-ventricular ejection time, and cumulative doses of catecholamines (epinephrine), enoximone, and furosemide.

Results. No hemodynamic variable showed any significant difference between aprotinin and placebo groups. Urine output, creatinine, lactate, and elastase levels, as well as the cumulative doses of furosemide and epinephrine were not significantly different. Twelve hours after CPB 10 patients in the placebo group and 4 in the aprotinin group had received enoximone (p < 0.05). The placebo group had received significantly larger doses of enoximone than the aprotinin group at arrival in the intensive care unit (0.13 ± 0.05 versus 0 mg/kg), 12 hours after CPB (0.58 ± 0.14 versus 0.18 ± 0.09 mg/kg), 24 hours after CPB (1.11 ± 0.24 versus 0.42 ± 0.16 mg/kg), and 48 hours after CPB (1.61 ± 0.40 versus 0.86 ± 0.28). At 6 hours the difference did not reach statistical significance.

Conclusions. Clinical and hemodynamic status of the aprotinin-treated patients was similar to that of the placebo-treated patients in the first 48 hours after CPB. The placebo group, however, required significantly more inotropic support by enoximone than the aprotinin group to achieve this goal.

	Introduction

Top Abstract Introduction Material and methods Results Comment References

 
Aprotinin is frequently used to reduce blood loss and for transfusion requirements after cardiac operations with cardiopulmonary bypass (CPB) [1,2]. Besides these beneficial effects some studies found that aprotinin therapy might have a protective effect on the myocardium. Treatment of the isolated rat heart with aprotinin before ischemia resulted in less myocardial damage [3], and patients who had CPB treated with aprotinin [4] had lower troponin T levels, indicating reduced myocardial damage. The purpose of our study was to evaluate the effects of perioperative aprotinin treatment on hemodynamics and the requirements for inotropic medications in pediatric patients who had surgical treatment of congenital heart disease.

	Material and methods

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Study protocol
A randomized, double-blind, placebo-controlled study was done in infants and children with congenital heart disease scheduled for cardiac operations with cardiopulmonary bypass (CPB). The study was approved by the local ethics committee, and all parents gave written informed consent. Half of the patients received aprotinin and half saline 0.9%. After induction of anesthesia and a small test dose, the patients randomly assigned to the aprotinin group received an initial dose of 28,000 KIU/kg (3.9 mg/kg) (Trasylol, Bayer AG, Leverkusen, Germany) followed by a continuous infusion of 7,000 KIU/kg (1 mg/kg) per hour. An additional 28,000 KIU/kg aprotinin were added to the priming solution of the bypass circuit. Patients in the placebo group received equal volumes of saline 0.9%. If there were clinical signs, hemodynamic data, or biochemical data of low cardiac output despite an optimized preload (left atrial pressure > 8 to 10 mm Hg) and despite an adequate heart rate, epinephrine was used to enhance contractility. Dopamine was only given in low doses (2.5 µg/kg per minute) to support urine output. If the signs of low cardiac output persisted despite this supportive therapy, enoximone was added as an inotropic and vasodilating medication. The decision to start these therapies was made according to the clinical judgments of the anesthesiologist and intensive care physician treating the child; they were not aware whether the patient had received aprotinin or placebo.

In all patients the following variables were recorded after arrival at the pediatric intensive care unit 6, 12, 24, and 48 hours after weaning of CPB: heart rate, mean blood pressure, left atrial pressure, central-to-peripheral temperature difference, urine output, serum lactate, and creatinine and neutrophil elastase levels. Two Doppler echocardiographic studies were obtained at the respective time points to evaluate myocardial performance: shortening fraction and the relation of preejection period to left ventricular ejection time (PEP/LVET). Cumulative doses (per kilogram of body weight) of the following medications were recorded at the same time points: epinephrine, enoximone, and furosemide. The cumulative doses were used because they represent better the support than the actual dose at a given time point, which can change rapidly.

Patients
The study population consisted of 34 infants and children aged 6 days to 15.2 years (mean, 2.5 years) with body mass of 3.2 to 32 kg (mean, 10.9 kg). There were 8 girls and 9 boys in the aprotinin group and 10 girls and 7 boys in the placebo group (Table 1). The surgical procedures performed are given in Table 2. There were no major complications or perioperative deaths. Mean cardiopulmonary bypass times were 133 minutes (range, 60 to 295 minutes). There were no significant differences between the groups with respect to age, weight, sex, aortic cross-clamp time, and bypass time (Table 1).

	Results

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All hemodynamic variables did not differ significantly between the aprotinin and the placebo groups. Mean arterial blood pressure was kept constant in both groups, with the nadir 12 hours after CPB. Left atrial pressure increased in both groups from 9 ± 0.6 mm Hg to 12 ± 0.7 mm Hg after 24 hours (Fig 1). Shortening fraction increased without significant differences in both groups from 28% ± 2.6% to 33% ± 2.0% (Fig 1); similarly, PEP/LVET decreased from 0.53 ± 0.004 to 0.48 ± 0.002. The central-peripheral temperature difference decreased from 8.5° ± 0.6°C to 4.0° ± 0.5°C and serum lactate from 3.1 ± 0.3 to 1.1 ± 0.1 mmol/L each without significant differences between the two groups. Elastase levels showed an initial peak at arrival to the intensive care unit of 142.3 ± 16.1 ng/mL; they declined at 12 hours to 95.8 and showed a secondary peak after 48 hours of 189.6 ± 24.7 ng/mL, each without significant differences between the two groups.

View larger version (29K): [in this window] [in a new window]   Fig 1. Left atrial pressure (LAP), shortening fraction, cumulative epinephrine dose [µg/kg], and cumulative enoximone dose [mg/kg] on arrival at the intensive care unit (ICU) 6, 12, 24, and 48 hours after weaning from bypass in the aprotinin group (closed circles) and placebo group (open triangles). There were no significant differences between the two groups in LAP and the cumulative epinephrine dose. The shortening fraction in the placebo group was reduced immediately postoperatively but did not reach significance. With the exception of 6 hours after bypass the placebo group received more enoximone. Values are shown as mean ± standard deviation. (ns = not significant; * p < 0.05).

Twelve hours after CPB 10 of 17 patients in the placebo group and 4 of 17 in the aprotinin group had received enoximone (p < 0.05). Patients in the placebo group had received significantly larger doses of enoximone at arrival in the intensive care unit (0.13 ± 0.05 versus 0 ± 0 mg/kg), 12 hours after CPB (0.58 ± 0.14 versus 0.18 ± 0.09 mg/kg), 24 hours after CPB (1.11 ± 0.24 versus 0.42 ± 0.16 mg/kg), and 48 hours after CPB (1.61 ± 0.40 versus 0.86 ± 0.28 mg/kg) than patients in the aprotinin group (p < 0.05) (Fig 1). Six hours after CPB this difference did not reach statistical significance.

	Comment

Top Abstract Introduction Material and methods Results Comment References

 
Both groups showed the same clinical, hemodynamic, and laboratory changes in the first 48 hours after CPB with no significant differences between the groups. These changes are well known and described. The placebo group, however, received significantly more inotropic support by the phosphodiesterase inhibitor enoximone than the aprotinin group to attain a similar hemodynamic profile. Phosphodiesterase inhibitors have been shown to improve cardiac index in infants with low cardiac output after cardiac operations [5]. Unfortunately we could not measure cardiac output. Thus a detailed algorithm for the use of enoximone in these heterogeneous patients was not practical. However, this affects both groups similarly because of the randomized, double-blind, placebo-controlled study design. Although the demographic data and baseline characteristics of the two groups were not significantly different, the patients in the aprotinin group were a little older and had shorter cross-clamp times. These differences might have influenced the results, and further studies are necessary.

Similar beneficial clinical effects were reported in other studies. In patients who had aortic arch replacement, who were treated with aprotinin and prostaglandin E1 a superior recovery of cardiac function was observed compared with the control group [6]. Aprotinin treatment in children led to a reduced number of patients with low cardiac output (10% versus 30% in the placebo group) and with arrhythmias (30% versus 60% in the placebo group) [7]. Aprotinin similarly prevented an alteration of cardiac function in an animal model of hemorrhagic shock [8]. A cardioprotective effect of aprotinin after aortocoronary bypass grafting has been noted, because patients treated with aprotinin had lower troponin T values than those in the control group [3]. Also in isolated hearts, preischemic treatment with aprotinin resulted in better contractility and reduced release of creatinin kinase MB [4,9]. Only one experimental study showed negative effects of aprotinin on the ischemic myocardium [10]. However this study was a model of coronary artery occlusion with myocardial infarction, which cannot be compared with cardioplegic cardiac arrest.

Several observations might explain the cardioprotective effect of aprotinin. 1) In isolated canine cyclic hearts the c-AMP and adenosine triphosphate contents were significantly higher when the cardioplegic solution contained aprotinin compared with control hearts [11]. The inotropic effect of enoximone is mediated by the inhibition of the breakdown of c-AMP thus increasing the amount of c-AMP in the heart. This result supports our finding that the placebo group required higher enoximone doses. 2) During CPB, free oxygen radicals are formed, which might cause myocardial dysfunction [12]. Perioperative aprotinin therapy resulted in reduced formation of oxygen radicals in children [7] and adults [13]. In cultured cardiac myocytes aprotinin similarly prevented the hydrogen peroxide-induced reduction in catalase, which is important, because catalase prevents the cytotoxicity of hydrogen peroxide [14]. 3) Aprotinin therapy prevents the release of lysosomal enzymes [9], which could lead to myocardial damage [15]. 4) During CPB the cytokines tumor necrosis factor- and interleukin-6 are formed [16], which have negative inotropic effects [16,17]. Aprotinin has been reported to reduce tumor necrosis factor- [18] and interleukin-6 [19] generation during CPB. 5) Aprotinin reduces thromboxane A₂ formation during CPB [20]. Thromboxane A₂ has been reported to have negative effects on cardiac function [21]. 6) During CPB nitric oxide production increases [22], in part by the cytokine-induced nitric oxide synthase that partially causes myocardial reperfusion injury [23]. Aprotinin therapy can reduce induced nitric oxide synthase iNOS expression and nitric oxide production [24].

In the peripheral circulation aprotinin inhibits kallikrein and thereby the formation of vasodilating bradykinin but also of vasoconstricting angiotensin II. However, the overall hemodynamic effect in animals with sepsis was increased blood pressure [25].

Aprotinin is a broad serine protease inhibitor, thus it is not unlikely that several of these mechanisms have effects. From our data we cannot conclude which of these effects is most important. Neutrophils have been reported to have an effect on post-CPB myocardial dysfunction. In the present study we found no difference in serum neutrophil elastase levels. These levels might not represent the situation in the reperfused heart. Aprotinin has been reported to have only a weak inhibitory effect on neutrophil elastase.

We have shown that patients treated with high-dose aprotinin therapy require less inotropic support with phosphodiesterase inhibitors after corrective procedures for congenital heart disease using CPB. Further studies are required to examine the protective effect of aprotinin in a larger number of patients.

	References

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