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Ann Thorac Surg 2004;77:962-967
© 2004 The Society of Thoracic Surgeons

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Original article: cardiovascular

Changes in hemostasis during pediatric heart surgery: impact of a biocompatible heparin-coated perfusion system

^a Department of Pediatric Anesthesiology and Intensive Care, Sahlgrenska University Hospital, Gothenburg, Sweden
^b Department of Anesthesiology and Intensive Care, Sahlgrenska University Hospital, Gothenburg, Sweden
^c Department of Cardiothoracic Surgery, Sahlgrenska University Hospital, Gothenburg, Sweden

Accepted for publication September 4, 2003.

^* Address reprint requests to Dr Jensen, c/o Intendent Wivi Linder, Department of Cardiothoracic Surgery, Sahlgrenska University Hospital, S-41345 Gothenburg, Sweden;
e-mail: ev.jensen{at}telia.com

	Abstract

Top Abstract Introduction Patients and methods Results Comment Conclusions Acknowledgments References

 
BACKGROUND: This study describes the response in hemostasis during open-heart surgery with cardiopulmonary bypass (CPB) in children ( 10 kg) and tests the hypothesis that the use of a biocompatible perfusion system, in comparison with a conventional system, causes less hemostatic activation.

METHODS: Prospective, randomized, controlled clinical study. Forty consecutive children 10 kg were included and divided into two groups: group bioc. (n = 19) treated with a fully heparin-coated system, centrifugal pump, and a closed circuit, and group conv. (n = 21) treated with an uncoated system, roller pump, and a hard shell venous reservoir. Concentrations of plasma thrombin-antithrombin (TAT), D-dimer, tissue plasminogen activator antigen (t-PA ag), and the complex consisting of tissue plasminogen activator and its inhibitor plasminogen activator inhibitor-1 (t-PA-PAI-1) were measured.

RESULTS: The biochemical variables measured increased significantly in both groups during the study period. There was less activation of fibrinolysis during cardiopulmonary bypass (t-PA ag: p = 0.009) in patients treated with the biocompatible perfusion system than in patients treated with the conventional system. A trend in favor of the biocompatible system based on the D-dimer and TAT data (p = 0.07 for both measurements) was observed but no significant intergroup differences regarding these variables or t-PA-PAI-1 were found.

CONCLUSIONS: Open-heart surgery with cardiopulmonary bypass in children ( 10 kg) causes transient activation of the coagulation and fibrinolytic systems. This study demonstrates that the use of a biocompatible perfusion system results in a lower extent of activation of fibrinolysis during CPB than the use of a conventional system.

	Introduction

Top Abstract Introduction Patients and methods Results Comment Conclusions Acknowledgments References

 
Bleeding after open-heart surgery with cardiopulmonary bypass (CPB) in children is a major cause of hemodynamic instability and of morbidity [1, 2]. This bleeding is the result of activation of the coagulation and fibrinolytic cascades, platelet dysfunction, profound hemodilution, and hypothermia during the procedure [3].

Reports from trials in adults suggest that the use of a biocompatible system with heparinized surfaces results in less activation of coagulation and fibrinolysis [4–6]. There is little information concerning activation of hemostasis (particularly regarding fibrinolysis) during CPB in neonates and infants especially when comparing the effect of different perfusion techniques. Results from adult trials cannot be extrapolated to young children because of age- and disease-dependent physiologic differences in hemostasis [7, 8]. The role of the cardiopulmonary system might be of greater importance in young children than in adults due to the relatively large blood–artificial surface interface. In this study we have combined three components in which previous experimental and clinical work has shown superior biocompatibility compared with conventional equipment [9–13]. It was assumed that this system would provide the best biocompatibility available at the time.

The aims of the present study were to describe the response in hemostasis during open-heart surgery with cardiopulmonary bypass in children ( 10 kg) and to test the hypothesis that the use of a biocompatible perfusion system, in comparison with a conventional system, causes less hemostatic activation. Measurements indicating activation of hemostasis were restricted to variables reflecting coagulation and fibrinolysis to minimize sample size in small children.

	Patients and methods

Top Abstract Introduction Patients and methods Results Comment Conclusions Acknowledgments References

 
Patients with congenital heart defects, body weight 10 kg, an estimated perfusion time exceeding 60 minutes, and a target cooling temperature of 28°C or less were included in the study. Patients on medication known to interfere with coagulation were excluded as were patients with Down's syndrome because they have a different inflammatory response to CPB than other children with congenital heart disease [14]. Forty consecutive children fulfilling the inclusion criteria were included in this prospective study. Clinical and demographic data are presented in Table 1.

Cardiopulmonary bypass technique
Before cannulation all patients were heparinized [activated clotting time (ACT) more than 480 seconds]. Hepcon HMS (Medtronic Inc, Minneapolis, MN), autodose mode, was used for monitoring of anticoagulation and calculation of heparin doses during the procedure. The ACT was kept above 480 seconds in all patients throughout CPB. At the end of CPB the protamine dose used for heparin reversal was determined on the basis of whole blood heparin concentration estimated by means of heparin–protamine titration. To eliminate the risk of residual heparin this test was repeated 10 and 60 minutes after the initial protamine dose. CPB was performed with nonpulsatile flow at a minimum rate of 2.8 L · min^-1 · m^-2. A Minimax Plus hollow fiber membrane oxygenator (Medtronic, Anaheim, CA) was used in both groups. The priming solution was composed of 150–300 mL of buffered electrolyte solution (Ringeracetat, Fresenius-Kabi, Sweden), 100 mL albumin, 200 mg/mL, 50–100 mmol of a buffer solution (Tribonat, Fresenius-Kabi, Sweden), 2 mL/kg mannitol (150 mg/mL), and 100 U/kg heparin. Erythrocyte concentrate was added in order to achieve a hematocrit between 20%–25%. Blood gases were continuously monitored in venous and arterial tubing using a blood gas analyzer for invasive monitoring (CDI400; Cardiovascular Device Instruments, Anaheim, CA). PvO₂ was kept above 4.5 kPa and blood gas regimen was performed using -stat management. Cardio-protection was achieved with intermittent cold blood cardioplegia (4°C). There was no restriction in use of cardiotomy suction. Temperature in nasopharynx and rectum was continuously monitored. Surgery was performed with hypothermia (< 20°C/3 pat, 20°C/3 pat, 25°C/13 pat, 28°C/21 pat). The 6 patients operated on at the lowest temperatures were equally distributed between the two groups studied. Weaning from CPB was commenced at a rectal temperature of 36°C. All patients but one were treated with modified (Great Ormond Street) ultrafiltration (hemofilter FH22; Gambro, Sweden) immediately after CPB (the exception was for technical reasons) [15]. The filter used for hemofiltration was not heparinized because, according to the manufacturer, this was not within the range of possibility (Medtronic Inc, Minneapolis, MN). Prophylactic treatment with tranexamic acid (30 mg/kg given before surgery and after CPB at the same time as protamine) or aprotinin (given in the CPB circuit, 10000 KIU/kg, and as an infusion starting before surgery, 10000 KIU/kg/20 minutes followed by 10000 KIU · kg^-1 · h^-1) was given if decided by the surgeon. One patient in the biocompatible group (=group bioc.) received aprotinin and 4 patients received tranexamic acid. Five patients in the conventional group (=group conv.) received tranexamic acid.

Study protocol
The patients were randomly allocated to one of the two regimens using a computerized program for randomization with sequential allocation depending on weight, age, gender, and preoperative oxygen saturation. The study protocol was approved by the Research Ethics Committee of the Medical Faculty, Göteborg University. Informed consent was obtained from the parents of the children studied.

One regime (group bioc., n = 19) comprised an extracorporeal system with a centrifugal pump (Biomedicus; Medtronic Inc, Minneapolis, MN) and a closed fully heparinized circuit (Carmeda Bioactive Surface, CBAS; Medtronic Inc, Minneapolis, MN). The other regime was a conventional nonheparinized system with a hard shell venous reservoir (Minimax; Medtronic Inc, Minneapolis, MN) and a roller pump (group conv., n = 21).

Blood samples for measuring the concentrations of thrombin–antithrombin (TAT), D-dimer, tissue plasminogen activator antigen (t-PA ag), and the complex consisting of tissue plasminogen activator and its inhibitor plasminogen activator inhibitor-1 (t-PA-PAI-1) were drawn from the arterial line on four occasions: after induction of anesthesia, after rewarming at 35°C, 1 hour after CPB and in the morning of the first postoperative day (POD1). All samples were drawn into tubes with Stabilyte^TM (Biopool AB, Ume, Sweden) and 0.129 mol/L sodium citrate (Venoject, Terumo Europe, Leuven, Belgium). Immediately after collection the blood samples were centrifuged and plasma was stored in individual tubes at -60°C for later analysis. The assays were performed in duplicate. Samples for measuring hemoglobin, leukocyte count, and platelet count were drawn on the same occasions. Concentrations of free plasma hemoglobin were measured 1 hour after CPB as a marker of hemolysis.

The plasma concentrations of TAT, D-dimer, t-PA ag, and t-PA-PAI-1 were determined by enzyme-linked immunosorbent assay (ELISA). The assays were performed according to the manufacturer's recommended procedure. The following assays were used: TAT (Dade Behring, Marburg, Germany) with the coefficient of variation between days being 9.1% for 25 ng/mL at ten occasions. Pooled normal plasma had a value of 1–4 ng/mL. D-dimer (Biopool AB, Ume, Sweden) with the coefficient of variation between days being 9% for 280 ng/mL on ten occasions. Pooled normal plasma had a value of 39.6 ng/mL, normal values below 400 ng/mL. t-PA ag (Biopool AB, Ume, Sweden) with the coefficient of variation between days being 7.7% for 18.3 ng/mL on ten occasions. The reference value for pooled plasma was 14.1 ng/mL. t-PA-PAI-1 (Biopool AB, Ume, Sweden) was used with the coefficient of variation between days being 11.4% for 9.7 ng/mL on ten occasions. Pooled normal plasma had a value of 4.6 ng/mL.

Statistical analysis
Data are presented as means ± standard errors of the mean (SEM) and 95% confidence intervals for intergroup differences. Differences in clinical variables between groups were tested using the Student t test, Mann–Whitney U test, or the Fischer exact test. Repeated measures were analyzed using multiple analysis of variance (MANOVA) for repeated measures. Differences between groups were analyzed using MANOVA for repeated measures followed, if significant for group effect or effect of interaction between group and time by the Student t test for each sample. p values < 0.05 were considered statistically significant.

	Results

Top Abstract Introduction Patients and methods Results Comment Conclusions Acknowledgments References

 
Clinical course
Clinical and demographic data are presented in Table 1. All patients included had the operation scheduled as the first case of the day. They all survived the perioperative and postoperative periods. Dopamine was used in all patients during the early postoperative hours. Nitric oxide therapy was used postoperatively in 3 patients in each group owing to pulmonary hypertension. Three patients had late closure of the sternotomy in group bioc. compared with five in group conv. Seven patients in group conv. had major bleeding ( > 5 mL · kg^-1 · h^-1) during the first 12 hours postoperatively as compared with 3 patients in group bioc. Three patients were reexplored in group conv. because of excessive hemorrhaging. None of them showed any obvious bleeding source attributable to inadequate surgical hemostasis. One of these patients developed a heart tamponade with circulatory arrest attributable to the bleeding. This patient had to be reexplored twice during the first 24 hours. One patient in group conv. underwent reoperation on the evening of postoperative day one because of the suspicion of an embolus in the right atrium that turned out to be a hematoma. No patient demonstrated symptoms of thromboembolic complication. One patient in group conv., who was operated on because of total anomalous pulmonary venous return, had to be reintubated 4 days after the initial extubation. This patient remained in the intensive care unit for 21 days due to sepsis and arrhythmia. The other patients all had a postoperative course within the normal range. There were no significant differences in postoperative clinical variables between the groups (Table 2).

	Comment

Top Abstract Introduction Patients and methods Results Comment Conclusions Acknowledgments References

 
Our results show that in young children ( 10 kg) open-heart surgery with CPB causes transient activation of the coagulation and fibrinolytic systems. Furthermore activation of fibrinolysis during CPB is reduced when using a biocompatible perfusion system in comparison with a conventional system.

Descriptive part of the study
Physiologic activation of blood coagulation is mediated almost exclusively via the tissue factor pathway and t-PA is the major physiologic activator of fibrinolysis. However CPB is not a physiologic condition and blood is exposed to nonbiological surfaces. Under these circumstances contact activation also plays an important role for activation of both coagulation and fibrinolysis. The hemostatic system in young children differs from that of older children although near adult values of coagulation factors are achieved by 6 months of life [7]. In spite of this fact the findings in our study, with activation of coagulation and fibrinolysis during CPB followed by a shut down in both systems postoperatively, resemble findings in older children as described by other investigators [2, 16]. Even when we scrutinize the neonates (n = 6) in our study separately we find the same pattern. This differs from the findings of Petäjä and colleagues who reported sustained consumptive coagulopathy after CPB and no activation of fibrinolysis in neonates during bypass but late activation on postoperative day 3 [17]. One probable explanation of this difference is the use of aprotinin in all patients in their study. Aprotinin inhibits transformation of plasminogen to plasmin which prevents production of D-dimer. This blockade of formation of D-dimer was also seen in the children (five in each group) who got fibrinolytic inhibitors (aprotinin and tranexamic acid) in our study. The inhibitors used have no effect on release of t-PA which is produced in an earlier stage in the fibrinolytic cascade.

Jaggers and colleagues have described CPB in small children as a procoagulant state. This was confirmed in our study [18]. Increased concentrations of TAT indicate a hypercoagulant state with enhanced thrombin generation and its subsequent inhibition. The observation that hypoxic children (saturation < 90%) had higher initial levels of TAT and t-PA ag indicates a state with consumptive coagulopathy in these children.

This is in line with the observation of Levin and colleagues, who reported evidence of supranormal coagulation activation in cyanotic children before surgery [19]. Hypoxia stimulates the endothelial cell to express tissue factor on its surface [18].

Comparison between groups
The fact that a fully heparin-coated biocompatible CPB system induces reduction in activation of fibrinolysis in young children during CPB has not, to our knowledge, been reported previously. The use of biochemical markers makes it possible to discriminate between activation of coagulation and activation of fibrinolysis. In clinical practice, as during CPB, simultaneous activation of both systems occurs [3]. t-PA production must be preceded by activation of the coagulation cascade. One might speculate that our finding is secondary to less activation of coagulation which would result in less production of fibrin when using a biocompatible perfusion system. Our results are not conclusive in this respect. However our data show a clear trend in favor of the biocompatible system based on the D-dimer and TAT data (p = 0.07 for both measurements) and the confidence intervals given in Table 3 suggest that even great differences in favor of the biocompatible system could be thinkable.

Another interpretation might be that the CPB system used leads to an isolated reduction in fibrinolysis, independent of fibrin formation caused by an increased inhibition of t-PA. This could give rise to a potentially harmful situation causing an imbalance in hemostasis. No such indications were found as there were no thromboembolic complications.

There is no doubt that part of the activation of thrombin during CPB is attributable to the massive tissue trauma caused by the surgical intervention (tissue factor activation) and this cannot be influenced by the perfusion system used. However as both pathways of activation of coagulation interact with inflammatory response, the use of a biocompatible CPB system might be of considerable value. Heparin-coated surfaces have been shown to reduce activation of both factor XII and the complement system [10, 20, 21]. Less activation of factor XII results in less production of kallikrein and bradykinin which leads to decreased secretion of t-PA from endothelial cells. The complement system affects both pathways of activation of the coagulation system.

Bleeding
No difference was found between the two groups in our study when comparing bleeding (ml/kg). With this in mind one can question the clinical importance of the reduction in activation of fibrinolysis found during CPB in the biocompatible system group. However there was a reduction in hemoglobin at the measurement 1 hour after bypass, more bleeding complications (three reoperations), and more patients who bled profusely during the first 12 hours postoperatively in the conventional system group. Calculations made on the basis of our results show that we would need a study three times the present size to be able to show a difference in bleeding with the power of 80%, p < 0.05.

Study design and limitations
The study design does not allow for evaluation of the role of the individual components of the bypass system. An alternative design where this would be possible would have required significantly greater resources. We reasoned that if the biocompatible bypass system used proved to be superior to the conventional system, this would motivate a more elaborate and resource-demanding protocol. Our findings, with a reduction in activation of fibrinolysis during CPB and a tendency towards reduction in TAT, D-dimer and bleeding certainly appear to encourage further investigations.

	Conclusions

Top Abstract Introduction Patients and methods Results Comment Conclusions Acknowledgments References

 
Open-heart surgery with cardiopulmonary bypass in children ( 10 kg) causes transient activation of the coagulation and fibrinolytic systems. This study demonstrates that the use of a biocompatible perfusion system results in a lower extent of activation of fibrinolysis during CPB than the use of a conventional system.

	Acknowledgments

Top Abstract Introduction Patients and methods Results Comment Conclusions Acknowledgments References

 
This study was supported by grants from the Swedish Heart and Lung Foundation and Göteborgs Läkarsällskap, Gothenburg, Sweden. Special thanks are given to Christina Linnér and Elsa Eriksson for laboratory assistance and to Anders Odén for advice on statistics.

	References

Top Abstract Introduction Patients and methods Results Comment Conclusions Acknowledgments References

 

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This Article Abstract Full Text (PDF) 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): Rolf Ekroth Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Jensen, E. Articles by Ouchterlony, J. Search for Related Content PubMed PubMed Citation Articles by Jensen, E. Articles by Ouchterlony, J. Related Collections Extracorporeal circulation