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Ann Thorac Surg 2003;76:129-135
© 2003 The Society of Thoracic Surgeons

Original article: cardiovascular

A prospective, double-blind study on the efficacy of the bioline surface-heparinized extracorporeal perfusion circuit

George M. Palatianos, MDa*, Christophoros N. Foroulis, MDa, Maria I. Vassili, MDb, George Astras, MDa, Konstantinos Triantafillou, MDa, Emmanuel Papadakis, MDa, Angela A. Lidoriki, RNa, Eugenia Iliopoulou, BScc, Efthimia N. Melissari, MDc

a Third Department of Cardiac Surgery, Onassis Cardiac Surgery Center, Athens, Greece
b Department of Anesthesiology, Onassis Cardiac Surgery Center, Athens, Greece
c Laboratory of Coagulation and Hemostasis, Onassis Cardiac Surgery Center, Athens, Greece

Accepted for publication February 13, 2003.

* Address reprint requests to Dr Palatianos, Onassis Cardiac Surgery Center, 356 Sygrou Ave, 176 74, Athens, Greece
e-mail: palatianos{at}otenet.gr


   Abstract
Top
 Abstract
Introduction
 Patients and methods
 Results
 Comment
 Acknowledgments
 References
 
BACKGROUND: We evaluated the newly introduced Bioline heparin coating and tested the hypothesis that surface heparinization limited to the oxygenator and the arterial filter will ameliorate systemic inflammation and preserve platelets during cardiopulmonary bypass (CPB).

METHODS: In a prospective double-blind study, 159 patients underwent coronary revascularization using closed-system CPB with systemic heparinization, mild hypothermia (33°C), a hollow-fiber oxygenator, and an arterial filter. The patients were randomly divided in three groups. In group A (controls, n = 51), surface heparinization was not used. In group B (n = 52), the extracorporeal circuits were totally surface-heparinized with Bioline coating. In group C (n = 56), surface heparinization was limited to oxygenator and arterial filter.

RESULTS: No significant difference was noted in patient characteristics and operative data between groups. Operative (30-day) mortality was zero. Platelet counts dropped by 12.3% of pre-CPB value among controls at 15 minutes of CPB, but were preserved in groups B and C throughout perfusion (p = 0.0127). Platelet factor 4, plasmin-antiplasmin levels, and tumor necrosis factor-{alpha} increased more in controls during CPB than in groups B or C (p = 0.0443, p = 0.0238 and p = 0.0154 respectively). Beta-thromboglobulin, fibrinopeptide-A, prothrombin fragments 1 + 2, factor XIIa levels, bleeding times, blood loss, and transfusion requirements were similar between groups. Intensive care unit stay was shorter in groups B and C than in controls (p = 0.037).

CONCLUSIONS: Surface heparinization with Bioline coating preserves platelets, ameliorates the inflammatory response and is associated with a reduced fibrinolytic activity during CPB. Surface heparinization limited to the oxygenator and the arterial filter had similar results as totally surface-heparinized circuits.


   Introduction
Top
 Abstract
 Introduction
Patients and methods
 Results
 Comment
 Acknowledgments
 References
 
Contact of blood with artificial surfaces during cardiopulmonary bypass (CPB) provokes a pathophysiological response similar to that of posttraumatic shock, the so-called "postperfusion syndrome" that may lead into the systemic inflammatory response syndrome (SIRS), adult respiratory distress syndrome, sepsis, and multiorgan failure [1]. To improve biocompatibility, artificial surfaces are heparin-coated with various materials in an effort to mimic the natural endothelial surface [1].

Heparin-coated artificial surface was first used by Gott [2]. The evidence that surface-heparinized equipment would not require full systemic heparinization led to the introduction of heparin-coated CPB circuits, in combination with reduced systemic heparin levels [3, 4]. Currently available heparin-coated circuits have been reported to be associated with reduced expression of SIRS; reduced activation of neutrophils, monocytes, eosinophils, platelets, and complement system; and limitation of cytokine release and reduced stimulation of the coagulation system [5–9]. However, clinical benefits have not been demonstrated in most studies on surface-heparinized circuits when full systemic heparinization is used [3, 10, 11].

Bioline coating (Jostra Medizintechnik, Hirrlingen, Germany) is a newer surface-heparinization method that is used to cover components of extracorporeal perfusion circuits [1]. Data on its clinical application are limited. In the present study, we evaluated the effectiveness of this newer surface coating. Because most platelet consumption in extracorporeal circuits takes place in the oxygenator and the arterial filter, we tested the hypothesis that surface heparinization limited to the oxygenator and the arterial filter will preserve platelets and will contribute to an amelioration of the systemic inflammatory reaction associated with CPB [12].


   Patients and methods
Top
 Abstract
 Introduction
 Patients and methods
Results
 Comment
 Acknowledgments
 References
 
Patients
One hundred fifty-nine patients (18 female) undergoing elective, first-time, isolated coronary artery bypass from December 1995 to March 2000 were prospectively randomized into three groups. In group A (n = 56 patients, controls) the extracorporeal perfusion circuit was not surface heparinized. In group B (n = 51 patients), a totally surface-heparinized extracorporeal circuit was used. Group C patients (n = 52) underwent perfusion with circuits in which only the oxygenator and the arterial filter were surface heparinized. According to our protocol, all patients had left ventricular ejection fraction higher than 0.30 and left ventricular end-diastolic pressure lower than 30 mm Hg. Exclusion criteria included insulin-dependent diabetes mellitus, coagulopathy, hepatic or renal dysfunction, chronic obstructive pulmonary disease, inflammatory or infectious diseases, a history of transient ischemic attacks or stroke, and use of nonsteroid antiinflammatory medications. Aspirin was discontinued at least 10 days before operation.

Patient characteristics and operative data are presented in Table 1. After surgery, the patients were transferred intubated to the intensive care unit (ICU) where a standard monitoring protocol was followed. The patients were discharged from the ICU if they had satisfactory postextubation arterial oxygenation and blood gas levels, and if they were hemodynamically stable without need for inotropic support. Red blood cell transfusions were administered if hematocrits were lower than 27%. Clinical measurement compared between groups were template bleeding times; amount of mediastinal blood loss the first 6 and 18 postoperative hours; need for blood and blood product transfusions; duration of mechanical ventilation; duration of ICU stay; incidence of early (30-day) postoperative complications; and length of postoperative hospitalization. Our Hospital’s Ethics Committee approved the study on June 30, 1995. Informed consent was obtained from each patient.


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  		Table 1. Patient Characteristics and Operative Data

 
Anesthesia
All patients received premedication with lorazepam 2.5 mg orally, 90 minutes before operation, morphine sulfate 0.1 mg/kg body weight intramuscularly, and ondansetron 8 mg orally 60 minutes before transfer to the operating room. Anesthesia was induced with midazolam (0.05 to 0.075 mg/kg), etomidate (0.3 mg/kg), and fentanyl (10 to 15 µg/kg). Neuromuscular block was induced by intravenous pancuronium (0.15 mg/kg) and was maintained by continuous infusion of cisatracurium (range 1.5 to 2.0 µg · kg-1 · min-1). Anesthesia was maintained using sevoflurane 0.5% to 2% in oxygen/air and additional boluses of fentanyl as needed or a continuous infusion of remifentanil 0.2 to 1.0 µg · kg-1 · min-1.

Cardiopulmonary bypass, myocardial protection, and surgical technique
The patients were put on closed-system CPB between the right atrium and ascending aorta at 33°C, with a roller pump (Stöckert-Shiley Instruments, Munich, Germany), a hollow-fiber membrane oxygenator (Quadrox, Jostra), and an arterial filter (HBF 40, Jostra). The extracorporeal circuits were either non–surface-heparinized (group A, control), totally surface heparinized (group B), or surface heparinized only in the oxygenator and the arterial filter (group C). Surface heparinization was achieved with the Bioline heparin coating that uses a high-molecular-weight heparin (Liquemin, Hoffman LaRoche, Basel, Switzerland) bound to a base-layer of immobilized recombinant human serum albumin adsorbed on hydrophilic or hydrophobic surfaces. With this heparinization method, a stable coupling of heparin is achieved by both covalent and ionic bonds, preserving the active sequence of heparin [1]. The extracorporeal circuits were prepared and packed by Jostra, and were sent to us numbered, without identification of the presence or extend of surface heparinization in a double-blind process. The type of extracorporeal circuit used for each patient and the group assignment were revealed after the completion of the clinical study, just before statistical analysis of the data.

The extracorporeal circuits were primed with 1000 mL Ringers lactate solution, 500 mL HAES-sterile 6% solution (Fresenius Kabi Hellas AE, Greece), 200 mL mannitol, 40 mEq sodium bicarbonate, and 10,000 Units of heparin (Leo Pharmaceutical Products, Denmark). Systemic anticoagulation was achieved with heparin sodium (250 to 300 U/kg body weight) and was monitored with repeated measurements of activated clotting time (ACT) using the Hemochron (International Technidyne, Edison, NJ). Cardiopulmonary bypass was initiated when ACT was longer than 480 seconds. Activated clotting time levels were maintained at these levels throughout CPB with additional heparin, as needed.

Standard coronary artery bypass operations were performed. Myocardial protection was achieved with retrograde and antegrade infusion of cold blood (4°C) cardioplegia. Topical hypothermia with cold saline solution was also used. After discontinuation of CPB, heparin was neutralized with protamine sulfate (Leo). Quantitative determination of circulating heparin and assurance of complete heparin neutralization were achieved with the Hepcon HMS/HMS Plus blood analyser (Medtronic, Minneapolis, MN).

Hematological and biochemical measurements
All hematological and biochemical values were corrected for hemodilution according to hematocrit. The following measurements were evaluated in the first consecutive 147 patients of the study: Platelet and leukocyte counts were measured with a Coulter HMX hematology analyzer (Beckman-Coulter, USA); platelet factor 4 (PF4), and ß-thromboglobulin as indicators of platelet activation and degranulation were evaluated with enzyme-linked immunosorbent assay (ELISA) using kits commercially available (the Asserachrom PF4 and ß-thromboglobulin, respectively, Diagnostica Stago, Taverny, France); Activated factor XII (FXIIa) as indicator of contact system activation was also assayed with ELISA assay (Shields Diagnostics Ltd, Dundee, UK); Plasmin-antiplasmin complex (PAP) as indicator of activation of fibrinolysis was assayed with a sandwich ELISA method (Enzygnost PAP micro, Behring Diagnostics GmbH, Germany); Prothrombin fragments F 1 + 2 (F 1 + 2) as indicators of thrombin generation through proteolytic activation of prothrombin were assayed using sandwich ELISA (Enzygnost F1 + 2 kits, Behring, Germany); Fibrinopeptide-A (FPA) as a direct indicator of thrombin generation released from the proteolytic cleavage of fibrinogen to fibrin was assayed with ELISA (Asserachrom FPA, Diagnostica Stago, Taverny, France); tumor necrosis factor-alpha (TNF-{alpha}) as indicator of the systemic inflammatory response was measured with ELISA (TNF-{alpha} kits, Chromogenix, Möldnal, Sweden); Antithrombin III levels were measured with the Coatest Antithrombin (Kabi Diagnostica, Stockholm, Sweden). Prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT), and fibrinogen concentrations were measured with an automated IL-3000R coagulometer (Instrumentation Laboratory, Italy). Blood samples were obtained preoperatively after induction of anesthesia (point 1, base line) and intraoperatively, 5 minutes after heparin administration (point 2), 15 minutes after initiation of CPB (point 3), at the end of CPB (point 4), and 30 minutes after protamine administration (point 5). Blood samples were taken from a radial artery catheter and were centrifuged immediately. Serum or plasma samples were divided in aliquots and were stored at -80°C until batch testing.

Statistical analysis
Values (mean ± SD) were compared between these three groups using the one-way analysis of variance (ANOVA) test for normally distributed data, or the nonparametric ANOVA analogues (Kruskal-Wallis and median tests) when dealing with not normal distributions, and the t test and Wilcoxon test for comparisons between any two groups. Repeated-measures ANOVA (RM-ANOVA) was used for comparison of the hematological and biochemical measurements between the three groups over time. Student’s t test for comparison of normal distributions or signed rank test for comparison of not normal distributions were used to compare each time point value with the base line value within each group. The Fisher’s exact test was used for the comparison of the rate of complications between groups.


   Results
Top
 Abstract
 Introduction
 Patients and methods
 Results
Comment
 Acknowledgments
 References
 
Clinical measurements
Patient characteristics and operative data were similar between the three patient-groups (Table 1). Surgical (30-day) mortality was zero.

No significant difference was noted between groups in the volume of postoperative blood loss (443 ± 285 mL/6 hours) or in the volume or incidence of transfusions of red cells (mean incidence for all groups, 53.7%), fresh frozen plasma (44.7%), or platelets (10.1%). The duration of ICU stay was significantly longer among controls compared with groups B or C (p = 0.037, Kruskal-Wallis ANOVA). Length of postoperative hospitalization was similar between groups.

Major complications were observed in 21/159 patients (13.2%) without difference in overall postoperative morbidity between groups (p = 0.189, Fisher’s exact test). No difference was observed between groups in the incidence of each complication (Table 2).


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  		Table 2. Postoperative Complications

 
Hematological measurements
There was a significant difference between groups in the time progression of platelet counts, with groups B and C exhibiting preservation of platelet counts throughout CPB (p = 0.0127, RM-ANOVA). By contrast the control group and in comparison with the base line values, the mean platelet count dropped by 12.3% at 15 minutes of CPB (p = 0.0042) and by 4.8% at 60 minutes of CPB (p = 0.0872). In all three groups, platelet counts dropped 30 minutes after the administration of protamine without significant difference between groups (p = 0.837, RM-ANOVA) (Table 3).


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  		Table 3. Changes in Platelet and White Blood Cell Counts

 
White blood cells increased progressively in each group throughout CPB and after protamine administration (p < 0.0001, RM-ANOVA) because of an increase in neutrophils. White cell counts for patients in group C increased the most, with a maximal difference observed 30 minutes after protamine administration (p = 0.0032, RM-ANOVA) (Table 3).

Biochemical measurements
Levels of PF4 increased during CPB and 30 minutes after protamine in all patient-groups. Release of PF4 increased more rapidly during CPB in controls than in the other groups (p = 0.0443, RM-ANOVA), with maximal difference observed at 15 and 60 minutes of CPB (p = 0.024 and 0.028, respectively, ANOVA) (Table 4). ß-Thromboglobulin levels increased significantly during CPB, but without significant difference between groups (p = 0.1121, RM-ANOVA).


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  		Table 4. Changes in PF4, PAP, and TNF-{alpha} Levels

 
Fibrinopeptide A levels were reduced by 88.3% to 89.3% of base line values at 60 minutes of CPB and raised after protamine administration by 32.8% to 56.7% above base line without any significant difference between groups (p = 0.2351, RM-ANOVA). Plasmin-antiplasmin complex levels increased faster among control patients than among patients in groups B or C during CPB (p = 0.024, RM-ANOVA). The maximal difference was observed at 15 and 60 minutes of CPB (p = 0.046, p = 0.016 respectively). At termination of CPB, PAP levels were significantly higher among controls than in patient-groups B and C combined (p = 0.008, RM-ANOVA) (Table 4). Prothrombin fragments 1 + 2 levels tended to rise during CPB and after protamine administration without significant difference between groups (p = 0.2773, RM-ANOVA). Factor XIIa levels increased similarly during CPB in all patient groups (p = 0.3869, RM-ANOVA). Antithrombin-III levels remained within normal range without significant intraoperative changes in all groups (p = 0.240, RM-ANOVA).

Among controls, TNF-{alpha} levels showed a sharp increase at termination of CPB. The difference was significant when compared with groups B and C at the same time points (p = 0.0183, Kruskal-Wallis ANOVA) (Table 4).

Changes in clotting and bleeding times
No difference was noted in PT, APTT, TT, and ACT changes between groups. Also, no significant difference was noted in bleeding time changes when comparing preoperative values with those at 1 hour after the operation (Table 5).


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  		Table 5. Coagulation and Hemostasis Tests

 

   Comment
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Comment
Acknowledgments
 References
 
Platelet counts usually decrease during CPB. The efficacy of surface heparinization to preserve platelets is still controversial. Thus, whereas a 31.7% platelet count reduction after 30 minutes of CPB with Duraflo II-coated extracorporeal circuits has been recently reported, another group reported a significant platelet preservation in surface-heparinized circuits with the Carmeda Bioactive system [11, 13]. It is possible that these differences may be surface related due to different surface-heparinization methodology used. In our study, using Bioline-coated circuits, platelet counts were preserved completely during CPB with both totally and partially surface-heparinized extracorporeal circuits. It should be noted that as expected, surface heparinization did not prevent platelet consumption after protamine administration.

Platelet factor 4 levels were significantly lower in the groups perfused with either totally or partially surface-heparinized circuits than in the control group. This finding may suggest that a reduced platelet activation and release reaction occurred during perfusion with Bioline-coated circuits. However, such a trend was not observed with ß-TG, which was similarly increased in all three groups as reported in studies of other surface-heparinization methods [6, 13–15]. The possibility that such release was mainly from the disturbed vascular endothelium cannot be excluded. Bleeding times increased similarly in all three patient groups after the operation, indicating the total surgical effect on vascular endothelium and platelets, including the effect of protamine.

Surface heparinization did not alter factor XIIa levels, an observation suggesting no effect on contact system activation, as has been suggested previously [13]. Furthermore, surface heparinization did not prevent thrombin generation during perfusion as indicated by the absence of difference in F1 + 2 and FPA levels between groups. The absence of effect of surface-heparinized surfaces on thrombin generation has also been pointed out previously [13, 16, 17].

In our study, the lower PAP levels at the end of CPB in patients perfused with Bioline-coated circuits probably reflect a lower degree of activation of fibrinolysis. This outcome was not observed in studies using either the Duraflo II or the Carmeda method [13, 15]. Prevention of fibrinolysis activation in association with the observed preservation of platelet counts suggests a lower hemorrhagic tendency [14]. In the present study, however, no difference was noted in the amount of postoperative blood loss or in the need for blood-product transfusions between groups. This may have been due to the fact that our patients were low-risk cases and had short perfusion durations.

Postoperative blood loss and the need for transfusions have been addressed repeatedly in studies evaluating surface-heparinized extracorporeal circuits. A beneficial effect of surface heparinization has not been observed to date among patients undergoing full systemic heparinization [4, 6, 10, 11, 13, 14, 18–23]. Bleeding tendency after extracorporeal circulation is related to operative trauma, platelet consumption, and level of systemic heparinization. Only with reduced systemic heparinization, were postoperative bleeding and the need for transfusions reduced in surface-heparinized systems [4, 24, 25]. This approach is recommended by some for high-risk patients but does not have wide acceptance because of the substantial risk of thrombosis [26, 27].

The lower TNF-{alpha} levels observed after 30 minutes of perfusion with surface-heparinized circuits compared with controls suggest a reduced systemic inflammatory response in patients perfused with the Bioline-coated systems. This observation is common in most reports on various surface-heparinization methods [1, 5–9, 11, 16, 17, 28, 29]. Tumor necrosis factor-{alpha} is an important and sensitive mediator in the SIRS/sepsis cascade [18, 30]. The high standard deviation observed is related to the high patient-to-patient variability characteristic of this proinflammatory cytokine [18]. The reduced neutrophil counts observed in groups A and B further support our hypothesis regarding the reduced inflammatory response associated with use of Bioline heparin-coated circuits.

Our clinical results overall were satisfactory in all three groups because we tested low-risk patients undergoing elective operation. In addition, no significant differences were observed in the rate of postoperative complications between groups, a finding in agreement with most published studies evaluating surface-heparinized circuits in systemically heparinized patients [4, 6, 10, 11, 19, 26]. Few studies have shown a lower incidence of postoperative atrial fibrillation when surface-heparinized systems were used [10, 20]. A recent study evaluating the clinical effect of Duraflo II-heparinized circuits reported lower rates of renal and pulmonary complications with surface-heparinized circuits in subgroups of high-risk patients [21]. However, in another study, no clinical benefit was observed with the Duraflo II-heparin-coated system in patients who underwent redo cardiac procedures, using full systemic heparinization and aspiration of blood from the pericardial sac into the perfusion system [6]. All other studies (including the present study) showed that surface heparinization has no effect on postoperative morbidity in low-risk patients undergoing coronary artery revascularization.

In our study, the postoperative ICU stay was generally short, a finding that could be related to the fact that we enrolled low-risk patients. However, the ICU stay was shorter among patients perfused with a totally or partially heparinized circuit, suggesting that the reduced degree of systemic inflammation observed in these patients may have contributed to faster recovery. Reduced postoperative ICU stay was also observed in a multicenter study that evaluated the Duraflo II-heparinized system [21]. Seven other studies evaluating various other surface-heparinization techniques found no significant differences in ICU stay, duration of mechanical ventilation, and overall hospitalization [6, 10, 11, 18, 20, 22, 31].

In conclusion, our results suggest that Bioline-coated extracorporeal circuits are associated with platelet preservation, reduced activation of fibrinolysis, and lower TNF-{alpha} levels indicative of a reduced inflammatory response. Unlike other methods of surface heparinization, use of Bioline coating is associated with reduced PF4 release and reduced fibrinolysis during CPB. However, an effect of surface heparinization on surgical bleeding or on need for transfusions was not observed among these low-risk patients. The shorter ICU stay observed among patients perfused with Bioline-coated circuits could be attributed to the reduced systemic inflammation. Surface heparinization applied only to the oxygenator and the arterial filter appears to have similar effects with the totally surface-heparinized extracorporeal circuits.


   Acknowledgments
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Comment
 Acknowledgments
References
 
We thank Yannis Bassiakos, PhD, for the statistical analysis of the data. This study is dedicated to the memory of Gil Balentine, Clinical Perfusionist, for his participation in its design and execution.


   References
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Comment
 Acknowledgments
 References
 

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Perioperative Blood Transfusion and Blood Conservation in Cardiac Surgery: The Society of Thoracic Surgeons and The Society of Cardiovascular Anesthesiologists Clinical Practice Guideline
Ann. Thorac. Surg., May 1, 2007; 83(5_Supplement): S27 - S86.
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S. Gunaydin, K. McCusker, V. Vijay, S. Isbir, T. Sari, M. A. Onur, A. Gurpinar, A. Sezgin, M. F Sargon, T. Tezcaner, et al.
Comparison of polymethoxyethylacrylate-coated circuits with leukocyte filtration and reduced heparinization protocol on heparin-bonded circuits in different risk cohorts
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