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Ann Thorac Surg 1998;66:166-171
© 1998 The Society of Thoracic Surgeons

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Original articles: cardiovascular

Heparin-coated bypass circuits: effects on inflammatory response in pediatric cardiac operations

^a Thoraxcentre, University Hospital Rotterdam, Rotterdam, the Netherlands
^b Blood Interaction Research, University Hospital Groningen, Groningen, the Netherlands

Accepted for publication February 10, 1998.

Address reprint requests to Mrs Schreurs, Thoraxcentre, University Hospital Rotterdam, Bd 467, Dr Molewaterplein 40, 3015 GD Rotterdam, the Netherlands

	Abstract

Top Abstract Introduction Material and methods Results Comment References

 
Background. This study was designed to investigate whether clinical signs of the inflammatory response in pediatric cardiac patients are reduced by heparin-coated cardiopulmonary bypass circuits and how this could be explained by differences in the pathophysiologic mechanisms involved.

Methods. In a randomized, prospective study 19 patients underwent cardiopulmonary bypass either with Carmeda BioActive Surface bypass circuits (n = 9) or with identical noncoated circuits (control, n = 10). Clinical parameters were recorded during the first 48 hours after the start of operation. Blood samples for determination of terminal complement complex, soluble form of E-selectin, and beta-thromboglobulin were obtained perioperatively up to 24 hours after operation.

Results. All clinical and inflammatory mediators showed a tendency in favor of the group with heparin-coated circuits. When analyzed on a point-by-point basis there were significant differences in postoperative central body temperature, soluble E-selectin levels, and beta-thromboglobulin levels (all p < 0.05).

Conclusions. These data suggest that the use of heparin-coated cardiopulmonary bypass offers clinical benefit and tends to reduce the release of inflammatory mediators.

	Introduction

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Operations involving cardiopulmonary bypass (CPB) induce a complex systemic inflammatory reaction, partly caused by blood–material interaction in the CPB circuit [1, 2]. In this regard, heparin-coated CPB circuits have been studied extensively, and their improved biocompatibility has been well demonstrated. These studies, however, have been performed on adult patients [3–6]. Although the inflammatory response has been documented in children undergoing CPB [7, 8], literature data on the use of heparin-coated CPB circuits in these patients are scarce. Therefore, the present study was designed to investigate in small children (<10 kg) whether the use of heparin-coated CPB circuits could reduce the inflammatory response after open heart operation and whether a reduction of the appearance of markers of the inflammatory response could be shown.

	Material and methods

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Patients
Nineteen patients (9 boys, 10 girls) with a body weight of less than 10 kg, undergoing elective cardiac operations for different congenital anomalies, were prospectively enrolled in this study. Informed parental consent was obtained for all patients, according to the regulations of the hospital medical ethical committee. Patients were randomized into two groups. In group I patients were assigned to cannula-to-cannula Medtronic Carmeda BioActive Surface-treated CPB circuits (Medtronic, Annaheim, CA) (CBAS, n = 9). In group II patients were assigned to identical, but noncoated circuits (control, n = 10). Demographic and surgical data are shown in Table 1.

Cardiopulmonary bypass
The CPB circuit consisted of a Minimax hollow fiber oxygenator, Minimax collapsable venous reservoir, Intersept cardiotomy reservoir (all Medtronic), Biomedicus BP 50 centrifugal pumphead (Medtronic Biomedicus, Eden-Prarie, CO), and a Pall LPE 1440 arterial line filter (Pall, Porthmouth, UK). The circuit was primed with red blood cells, ABO fresh frozen plasma, and Ringer’s solution (Baxter, Utrecht, The Netherlands) to achieve an intraoperative hematocrit of 0.28 L/L. The prime was completed with 3,000 IU of porcine heparin (Leo Pharmaceutical Products, Weesp, The Netherlands), 0.5 g/kg body weight mannitol, and 0.5 g/kg body weight human albumin (CLB, Amsterdam, the Netherlands). Before cannulation patients were heparinized with 300 IU/kg body weight. Activated clotting time was measured with a Hemotec kaolin cartridge (Medtronic Hemotec, Parker, CO) and was maintained at more than 480 seconds during the procedure. Patients were systemically cooled to a nasophyaryngeal temperature of 25°C and weaned off CPB when rectal temperature reached 34°C. Blood flow rate was maintained at 2.4 L · min^-1 · m^-2 at normothermia and at 1.5 to 1.8 L · min^-1 · m^-2 at 25°C. Blood from the operating field was aspirated by vacuum-controlled cardiotomy suction (maximum, -60 mm Hg) and collected in the cardiotomy reservoir. Cardiotomy suction was kept to a minimum. At the end of CPB heparin was neutralized with protamine chloride (Kabi Pharmacia, Woerden, The Netherlands) at a dose of 4 to 5 mg/kg body weight.

Postoperative care
Postoperative goals were normal hemodynamic parameters according to patient age. Afterload reduction and inotropic support consisted of 2 µg · kg^-1 · min^-1 dopamine and 1 µg · kg^-1 · min^-1 nitroglycerin. Basic intravenous fluid administration consisted of 2 mL · kg^-1 · h^-1 glucose 5%. If urine production was less than 1 mL · kg^-1 · h^-1, 1 mg/kg furosemide was given. Kidney function was measured by serum and creatinine levels, liver function was measured by alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase, and -glutamyltransferase levels. Patient ambient temperature was kept at 36°C during the intensive care unit stay, with a Dräger radiant heater 600 W (Drägerwerk Aktiengesellschaft, Lübeck, Germany).

Postoperative inflammatory response
Postoperative central body temperature and increase of patient body weight were used as clinical parameters for the determination of the postoperative inflammatory response. To determine differences in body weight patients were weighed nude on a Sartorius QS 16 scales (Sartorius, Goettingen, Germany) immediately before the operation. Patients were weighed again 24 hours after arriving at the intensive care unit in the same way as preoperatively. Central body temperature was monitored continuously by measuring rectal temperature during the first 24 hours postoperatively with a Lameris 5386249 temperature probe (Lameris, Veenendaal, the Netherlands). Fever was defined as a rectal temperature more than 38°C.

Blood collection and processing
Blood for determination of the inflammatory markers was collected in tubes containing 0.5 mol of EDTA and 2.5% polybrene. Tubes were immediately placed on ice. Samples were collected after induction of anesthesia, at 20 minutes on CPB, 5 minutes before and 5 minutes after release of the aorta cross-clamp, at termination of CPB, 20 minutes after protamine administration, and 24 hours after CPB. All samples were immediately centrifuged and plasma was stored at -40°C. Complement activation was indicated by the terminal complement complex and determined by an enzyme-linked immunosorbent assay (Quidel, San Diego, CA; normal value, <40 ng/mL; lower detection limit, 20 ng/mL). Platelet activation was indicated by ß-thromboglobulin (ßTG) and determined by radioimmunoassay (Amersham International, Amersham, UK; normal value, 20 to 30 ng/mL; lower detection limit, 10 ng/mL). Endothelial cell activation was indicated by the soluble form of E-selectin (sE-selectin) and determined by an enzyme-linked immunosorbent assay (R&D Systems, Abingdon, UK; normal value, 29 to 63 ng/mL; lower detection limit, 0.1 ng/mL).

Statistics
Data are expressed as mean value ± standard error of the mean. Student’s t test was performed to compare group differences. Because of repeated measurements in a limited number of patients in each group, comparisons were made by point-by-point analysis with a Mann-Whitney or Wilcoxon rank sum test. These data were completed by area under the curve analysis. A p value less than 0.05 was considered statistically significant.

	Results

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Perioperative data
There were no significant differences in baseline data between the two groups (Table 1). Postoperatively no complications occurred and all patients survived. There were no significant differences between the groups concerning intraoperative and postoperative blood loss, transfusion requirements, urine production, kidney or liver function, and duration of postoperative ventilatory support (Table 2).

View larger version (17K): [in this window] [in a new window]   Fig 1. Postoperative central body temperature in pediatric patients perfused either with the extracorporeal circuit with Carmeda BioActive Surface (CBAS, n = 9) or without (Control, n = 10). (Point-by-point analysis, *p < 0.05, **p < 0.01; area under the curve analysis, not significant).

View larger version (15K): [in this window] [in a new window]   Fig 2. Central body temperature at 4 hours and 12 hours in intensive care unit (ICU). Significant difference in patients with temperature above 38°C (at 4 hours CBAS 2 versus Control 7, p < 0.05; at 12 hours CBAS 0 versus Control 5, p < 0.01). (CBAS = Carmeda BioActive Surface.)

View larger version (14K): [in this window] [in a new window]   Fig 3. Terminal complement complex (TCC) during and after cardiopulmonary bypass (CPB) in pediatric patients perfused either with the extracorporeal circuit with Carmeda BioActive Surface (CBAS, n = 9) or without (Control, n = 10). Samples taken as described in the text. (PreCPB = after induction of anesthesia; 20'CPB = 20 minutes after start of CPB; -5'X-off = 5 minutes before declamping; 5'X-off = 5 minutes after declamping; endCPB = at termination of CPB; 20'Prot = 20 minutes after starting the administration of protamine.)

View larger version (16K): [in this window] [in a new window]   Fig 4. Soluble form of E-selectin (sE-Selectin) during and after cardiopulmonary bypass (CPB) in pediatric patients perfused either with the extracorporeal circuit with the Carmeda Bioactive Surface (CBAS, n = 9) or without (Control, n = 10). Samples taken as described in the text. (PreCPB = after induction of anesthesia; 20'CPB = 20 minutes after start of CPB; -5'X-off = 5 minutes before declamping; 5'X-off = 5 minutes after declamping; endCPB = at termination of CPB; 20'Prot = 20 minutes after starting the administration of protamine.) (Point-by-point analysis, *p < 0.05; area under the curve analysis, not significant).

View larger version (17K): [in this window] [in a new window]   Fig 5. ß-Thromboglobulin released from activated platelets during and after cardiopulmonary bypass (CPB) in pediatric patients perfused either with the extracorporeal circuit with the Carmeda Bioactive Surface (CBAS, n = 9) or without (Control, n = 10). Samples taken as described in the text. (PreCPB = after induction of anesthesia; 20'CPB = 20 minutes after start of CPB; -5'X-off = 5 minutes before declamping; 5'X-off = 5 minutes after declamping; endCPB = at termination of CPB; 20'Prot = 20 minutes after starting the administration of protamine.) (Point-by-point analysis, *p < 0.05; area under the curve analysis, not significant).

	Comment

Top Abstract Introduction Material and methods Results Comment References

As in the study by Ashraf and colleagues [12], the postoperative clinical course in the present study was positively modified after CPB by the use of heparin-coated circuits. However, they found an improvement on postoperative ventilation time. In our study ventilation time was limited in both groups. Our study showed a beneficial effect on postoperative central body temperature. Development of postoperative fever is often seen in young children undergoing CPB [10]. In our study postoperative central body temperature was lower in the CBAS group. This suggests that the heparin-coated CPB circuit improves the clinical condition of pediatric patients after cardiac operations in this respect.

Cardiopulmonary bypass in children is also associated with a capillary leak, which results in an increase in total body water after CPB [13, 14]. Longer duration of bypass, lower temperature, younger age, and lower body weight have been shown to be incremental risk factors of the accumulation of water [13]. Although results of this study show reduced postoperative gain in body weight in the CBAS group, this difference did not reach a level of significance. In this regard the overall perioperative fluid management plays an essential role and influences the possible beneficial effects of heparin-coated CPB. Moreover, in our study group the number of patients was small and the duration of CPB relatively short. Further investigations in neonates of low body weight undergoing longer periods of CPB are necessary to show significant differences in this respect. In our study we found no significant differences in complement activation. Concentrations of sE-selectin, however, a marker of endothelial activation, were lower in the CBAS group. Injury to the endothelial cells is a frequent outcome of the acute inflammatory response [15, 16], which may lead to extravasation of leukocytes and leakage of fluid in the extravascular space. As observed in this study, the baseline levels of sE-selectin in plasma, a marker of endothelial activation, were rather high, more than twice as high as levels of adults [6]. Concentrations decreased after initiation of CPB, even when mathematically corrected for hemodilution (data not shown). This pattern is in agreement with other articles in which adhesion molecules in a comparable group of pediatric patients were studied [17, 18]. The reason of these high baseline levels is still not clear. It might indicate some preexisting endothelial damage before operation [17]. The sE-selectin levels during CPB were lower in the CBAS group, when analyzed by point-by-point analysis. However, the mechanism and importance of lower sE-selectin concentrations in patients perfused with CBAS circuits remains uncertain.

The relevance of ßTG levels in relation to heparin-coated CPB is still not established. It is known that impaired hemostasis after CPB is mainly attributable to platelet damage [19]. Although in this study no beneficial effect was demonstrated in postoperative blood loss, ßTG levels were lower in the CBAS group, especially at the end of CPB. In addition to contact activation, other factors such as return of cardiotomy blood, contributes to a large extent to platelet damage. Consequently, this damage can partly obscure the improved biocompatibility of a heparin-coated circuit [20]. Therefore, in some studies cardiotomy suction is compensated by a red cell washing device. In our study we used cardiotomy suction without cell washing. Platelet activation remained less in the CBAS group as identified by lower ßTG levels. This suggests that the role of suction blood in obscuring the biocompatibility of extracorporeal circuits may be less important in children. The small amount of cardiotomy suction and the large biomaterial-to-blood ratio may explain this. Again larger study groups are necessary to support these findings.

Limitations of the study
Our study concerns a biological system with relatively large standard deviations in a limited number of patients and a limited number of observations. This hampers statistical analysis. Therefore, larger randomized studies will be necessary to further elucidate the efficacy of heparin-coated CPB during pediatric open heart operation.

Conclusion
Our data suggest that the use of heparin-coated CPB offers a clinical benefit and tends to reduce the release of inflammatory mediators during CPB.

	References

Top Abstract Introduction Material and methods Results Comment References

 

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