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Ann Thorac Surg 1996;61:1363-1366
© 1996 The Society of Thoracic Surgeons

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Original Articles: Cardiovascular

Heparin-Coated Circuits and Aprotinin Prime for Coronary Artery Bypass Grafting

Service de Chirurgie Thoracique et Cardiovasculaire, Centre Nacional de la Recherche Scientifique Unité de Recherche Associeé 1431, Hôpital Henri Mondor, Créteil, France

Accepted for publication January 8, 1996.

	Abstract

Top Footnotes Abstract Introduction Material and Methods Results Comment References

 
Background. The biocompatibility of an extracorporeal circuit is improved by heparin bonding onto its inner surface. To determine the effect of heparin-coated circuits for cardiopulmonary bypass with aprotinin prime on postoperative recovery and resource utilization, a prospective study was done in 102 patients undergoing coronary artery bypass grafting with full systemic heparinization.

Methods. Patients were randomly allocated to be treated with either a heparin-coated circuit (n = 51) or an uncoated circuit (n = 51). Differences in blood loss, need for blood transfusion, morbidity, and intensive care stay were analyzed.

Results. No differences in blood loss and need for blood transfusion were found between the groups. The relative risk for adverse events in the heparin-coated group was 0.29 (95% confidence interval ranging from 0.10 to 0.80). Adverse events included myocardial infarction (2 patients in the uncoated group versus 0 in the heparin-coated group), rethoracotomy for excessive bleeding (1 versus 2), rhythm disturbance (7 versus 2), respiratory insufficiency (4 versus 0), and neurologic dysfunction (2 versus 0). The lower incidence of adverse events in the heparin-coated group was associated with a shorter intensive care stay (median, 2 days; range, 2 to 5 days) compared with the uncoated group (median, 3 days; range, 2 to 19 days, p = 0.03). The cost savings of 1 day of intensive care stay counterbalanced the additional costs of heparin-coated circuits.

Conclusions. The use of heparin-coated circuits for cardiopulmonary bypass with aprotinin prime resulted in a significant reduction in morbidity in the early postoperative phase and a concomitant decrease in intensive care stay, resulting in important cost savings.

	Introduction

Top Footnotes Abstract Introduction Material and Methods Results Comment References

 
The humoral and cellular activation that occurs in association with cardiopulmonary bypass (CPB) induces a variable degree of organ dysfunction and bleeding disorders after otherwise uneventful cardiac operations [1, 2]. Postoperative bleeding is intensified in patients receiving aspirin in addition to other antianginal medication [3, 4]. The efficacy of aprotinin as a hemostatic agent during coronary artery bypass grafting is indisputable and has motivated many centers to use this drug in their CPB protocol, particularly in patients receiving aspirin [5–8].

Exposure of blood to the artificial surface of the extracorporeal circuit is the main source of complement activation during CPB [9, 10]. The degree of complement activation, as measured by concentrations of C3a and terminal complement complex C5b-9, has been associated with the incidence of postoperative cardiac, pulmonary, and renal dysfunction [10–12]. Recently, it has been demonstrated that heparin surface coating of extracorporeal circuits results in significant reduction in complement activation and, subsequently, in the inflammatory response [13–15]. However, little attention is paid to the clinical response to improved biocompatibility. Currently, heparin-coated circuits are commercially available and their relatively low price makes them attractive to use routinely in cardiac operations, particularly if a decrease in postoperative morbidity could be obtained.

The aim of this study was to investigate whether the use of heparin-coated circuits with aprotinin prime for elective coronary artery bypass grafting in patients receiving aspirin is associated with an improvement in postoperative recovery, as measured by hemostasis, incidence of adverse events, and intensive care (ICU) stay, the latter as a measure of resource utilization.

	Material and Methods

Top Footnotes Abstract Introduction Material and Methods Results Comment References

 
Design of the Study
Between October 1993 and October 1994, 102 patients receiving aspirin who were scheduled for elective coronary artery bypass grafting were randomly allocated to be treated with either a heparin-coated circuit or an uncoated circuit. Entry criteria for the study were (1) ingestion of aspirin for at least 7 days, with the last dose taken within 24 hours before operation, (2) left ventricular ejection fraction greater than 30%, (3) no history of rhythm disturbance, (4) no impaired organ function other than myocardial ischemia, (5) no insulin-dependent diabetes melllitus, and (6) no active inflammatory disease. Physicians involved in postoperative patient care were blinded for randomization. To improve concealment of treatment allocation, no deviation of perfusion protocols or additional blood sampling were introduced.

Clinical end points of the study were postoperative morbidity and duration of ICU stay. Major outcome measurements include incidence of postoperative adverse events, the number of postoperative days in the ICU, and cost-benefit estimation. Patients are usually discharged from the ICU when they are extubated, exempted from continuous monitoring and intravenous inotropic treatment, and after removal of chest tubes. The incidence of postoperative morbidity was used as a composite end point that was defined as the number of patients in each study group that develops new adverse events within 5 days after operation. Postoperative adverse events were identified as acute myocardial infarction (new Q waves in two or more contiguous leads on postoperative 12-lead electrocardiogram), intraaortic balloon pumping, rethoractomy for excessive bleeding, rhythm disturbances requiring prolonged monitoring (three-lead electrocardiogram) or medical treatment (amiodarone), respiratory insufficiency (more than 48 hours mechanical ventilation due to respiratory insufficiency), neurologic dysfunction (focal brain lesion confirmed by computed tomographic scan, diffuse encephalopathy, or coma), sepsis (positive blood culture), and renal dysfunction requiring dialysis. Volume of blood loss and the need for donor blood transfusion and vasoactive medication was measured from induction of anesthesia until 18 hours after the operation.

Anesthesia and Extracorporeal Circulation
Anesthesia was induced and maintained with phenoperidine and droperidol. The extracorporeal circuit consisted of a roller pump (Sarns 9000; 3M Health Care Group, Ann Arbor, MI), closed venous reservoir, hollow fiber oxygenator (Univox, Baxter, Irvine, CA), cardiotomy reservoir (Baxter BCR 3500), and arterial line filter (Baxter AF-1040). All compartments of the circuit in the heparin-coated group were treated with surface-bonded heparin (Duraflo II; Bentley Laboratories, Uden, the Netherlands). The extracorporeal circuit was primed with 1,000 mL of lactated Ringer's solution, 200 mL of aprotinin (2 x 10⁶ KIU Trasylol; Bayer, Leverkusen, Germany), 60 mL of 8.4% sodium bicarbonate, 5,000 IUAu: 5,000 units? bovine heparin , and 1 g potassium chloride. Heparin (300 IU/kg) was administered into the right atrium before cannulation. According to the hemodynamic situation, 500 to 1,000 mL of autologous blood was donated just before start of CPB. This autologous blood was reinfused after cessation of CPB. Cardiopulmonary bypass was performed with core cooling to 28°C and nonpulsatile flow of 2.4 L • min^-1 • m^-2. During aortic cross-clamping, the myocardium was protected with antegrade cold cardioplegia. All patients were operated by one of four surgeons in the thoracic and cardiovascular surgery unit of the Henri Mondor Hospital. Anticoagulation during CPB was controlled by measurement of the activated clotting time (Hemotec, Inc, Englewood, CO). Additional heparin was administered if the activated clotting time was less than 600 seconds. Volume supplementation was achieved by macromolecular solution or human albumin solution (4%). During CPB, all intrapericardial blood was reinjected into the patient through the aortic cannula. After cessation of CPB, protamine sulfate (1 mg per 100 IU heparin) was administered intravenously, followed by infusion of residual pump blood. Transfusion of packed red blood cells was indicated if the hematocrit value was less than 25%.

Data Analysis
Data were stored and analyzed with the use of standard computer software (Statview 4.02; Abacus Concepts, Berkeley, CA). Intergroup comparisons were assessed with unpaired t tests for continuous data (expressed as means with standard deviation) and the Mann-Whitney U test for discrete data (expressed as median with range). Differences in incidence of adverse events were analyzed with the Fisher exact test and estimation of relative risk (ratio with 95% confidence interval). Analysis of variance was used if appropriate. A two-tailed p value of less than 0.05 was considered to be statistically significant.

	Results

Top Footnotes Abstract Introduction Material and Methods Results Comment References

 
Patient characteristics and surgical data of both groups are listed in Table 1. Table 2 shows intergroup comparison of blood loss, blood use, hematocrit, use of vasoactive medication, and extubation timetab 2. No significant differences in these parameters were found between the groups.

	Comment

Top Footnotes Abstract Introduction Material and Methods Results Comment References

Originally, heparin coating of the inner surface of CPB circuits was introduced to enable low systemic heparinization, with an expected reduction in blood loss and transfusion requirements. However, von Segesser and colleagues [16, 17] have pointed out that low systemic heparinization during routine open heart operations has an indication in patients at risk for heparinization, but is safe only with adapted surgical techniques and strict regulations to prevent low flow areas in the circuitry.

The mechanism of the inhibitory effects of heparin coating on complement activation has not been revealed yet, but reduction in circulating C3a, C3b, and C5b-9 has been demonstrated repeatedly [15, 18, 19]. As a consequence of reduced complement activation, neutrophil release products like elastase, myeloperoxidase, and lactoferin were found in lower concentrations in patients treated with heparin-coated circuits [13, 15]. The diversity of mediators identified in connection with the inflammatory response to CPB impedes the determination of reduced complement activation in relation to patient morbidity. The role of complement activation in the pathogenesis of the so-called postperfusion syndrome is based on the findings of a frequently quoted study by Kirklin and colleagues [10]Au: ref # correct? who found a relation between high levels of C3a and postoperative morbidity, in particular pulmonary dysfunction. The correlation between C3a and respiratory complications was confirmed by others [12]. Previously, we found lower levels of C5b-9 in a group of patients treated with heparin-coated circuits in combination with a favorable postoperative recovery in these patients [20].

In the present study we avoided the challenge of identifying the individual mediators of the inflammatory response. Instead, in a routine setting we investigated as to whether the convalescence among aspirin receiving patients undergoing elective coronary artery bypass grafting with aprotinin prime was influenced by the use of heparin-coated circuits. The reduction in risk of postoperative morbidity was significant for the heparin-coated group, but larger sample sizes would be needed to reduce the width of the 95% confidence interval. The decrease of 1 day ICU stay in the heparin-coated group clearly counterbalanced the extra cost of heparin bonding of the circuit.

The absence of respiratory insufficiency in patients treated with heparin-coated circuits is worthy of comment. Although we did not include measurements of inflammatory mediators in this study, this finding suggests that complement activation, as being associated with respiratory complications [11, 12], might be inhibited in the heparin-coated group. As to whether mortality is reduced by the heparin coating our data are merely suggestive. Mortality is a crude measure that is determined by multiple patient-related factors and it is possible with the present sample size that the results are skewed by outlying patients. The use of heparin-coated circuits did not reduce any specific complications in this good-risk population. The number of days in the ICU are multifactorial after cardiac operation. As to whether our results can be translated into a larger surgical population that includes patients with high-risk conditions needs to be investigated. In such a population the use of heparin-coated circuits might ameliorate the postoperative course and, subsequently, the financial burden imposed by prolonged intensive treatment.

The preliminary results presented here urged us to extend our clinical study to a high-risk patient population, with implementation of biochemical studies to analyze the effect of heparin-coated circuits on the inflammatory response, its relation to aprotinin use, and the need for postoperative intensive treatment.

	Footnotes

Top Footnotes Abstract Introduction Material and Methods Results Comment References

 
Address reprint requests to Dr Jansen, Department of Cardiac Surgery L-325, University Hospital "Vrije Universiteit," PO Box 7057, 1007 MB Amsterdam, the Netherlands.

	References

Top Footnotes Abstract Introduction Material and Methods Results Comment References

 

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6. Van Oeveren W, Harder MP, Roozendaal KJ, Eijsman L, Wildevuur CRH. Aprotinin protects platelets against the initial effect of cardiopulmonary bypass. J Thorac Cardiovasc Surg 1990;99:788–97.[Abstract]
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11. Moore FD, Warner KG, Assousa S, Valeri CR, Khuri SF. The effects of complement activation during cardiopulmonary bypass. Ann Surg 1988;208:95–103.[Medline]
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13. Borowiec J, Thelin S, Bagge L, Nillson L, Venge P, Hansson HE. Heparin-coated circuits reduce activation of granulocytes during cardiopulmonary bypass. J Thorac Cardiovasc Surg 1992;104:642–7.[Abstract]
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15. Fosse E, Moen O, Johnson E et al. Reduced complement and granulocyte activation with heparin-coated cardiopulmonary bypass. Ann Thorac Surg 1994;58:472–7.[Abstract]
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This Article Abstract Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Piet G. M. Jansen Christophe Baufreton Daniel Y. Loisance Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Jansen, P. G. M. Articles by Wildevuur, C. R. H. Search for Related Content PubMed PubMed Citation Articles by Jansen, P. G. M. Articles by Wildevuur, C. R. H.