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J Thorac Cardiovasc Surg 2004;127:1458-1465
© 2004 The American Association for Thoracic Surgery

Surgery for congenital heart disease

Phosphorylcholine or heparin coating for pediatric extracorporeal circulation causes similar biologic effects in neonates and infants

^a Department of Cardiovascular Surgery, University Hospital, Kiel, Germany,
^b Department of Pediatric Cardiology, University Hospital, Kiel, Germany,
^c Institute of Medical Informatics and Statistics,^c University Hospital, Kiel, Germany

Received for publication April 22, 2003; revisions received August 14, 2003; accepted for publication August 18, 2003.

^* Address for reprints: Andreas Böning, MD, Department of Cardiovascular Surgery, University Hospital, Arnold-Heller-Str 7, 24105 Kiel, Germany
aboening{at}kielheart.uni-kiel.de

	Abstract

Top Abstract Patients and methods Results Discussion APPENDIX 1 References

 
OBJECTIVE: Cardiac surgery for complex congenital malformations with use of extracorporeal circulation predisposes to an excessive systemic inflammatory response and a consecutive capillary leak syndrome. In a prospective randomized study the influence of 2 oxygenators especially designed for pediatric use on inflammatory markers and clinical outcome was investigated.

METHODS: Forty neonates and infants (body surface area, <0.36 m²) undergoing cardiac surgery with extracorporeal circulation were randomized into one of 3 groups: in the first group (n = 14) the Medtronic Minimax Oxygenator and in the second group (n = 12) the Dideco Lilliput 1 Oxygenator, both with a 750-mL priming volume, were used. In the third group the Dideco Lilliput 1 Oxygenator was filled with a reduced priming volume of 450 mL. Parameters of interest for evaluation of a systemic inflammatory response after extracorporeal circulation were interleukin 6, tumor necrosis factor , neutrophil elastase, complement C3, and free hemoglobin. In addition, erythrocyte, leukocyte, and thrombocyte counts and hemoglobin and C-reactive protein values were determined at different measurement points before, during, and after the operation.

RESULTS: In all 3 groups peak values for tumor necrosis factor were observed during the operation, whereas interleukin 6, elastase, and free hemoglobin values peaked in the first 4 hours. The highest values for leukocytes and C-reactive protein were obtained between 24 and 72 hours after the operation. Erythrocyte and thrombocyte counts, as well as hemoglobin values, were lowest at extracorporeal circulation onset, normalizing under substitution in the first 4 hours after the operation. By using the Lilliput/750 oxygenator, higher interleukin 6 values 1 and 4 hours after the operation and higher tumor necrosis factor values during and 1 hour after the operation could be observed compared with results with the Minimax and Lilliput/450 oxygenators. In spite of our randomization protocol, patients in the Lilliput/750 group were significantly smaller and younger than those in the Minimax group. However, the statistical analysis showed no correlation between age and interleukin 6 or tumor necrosis factor values, but it did show a correlation between younger age and the occurrence of capillary leak syndrome. Accordingly, the number of children with clinically complicated course (capillary leak, longer duration of catecholamine therapy, and ventilation) was higher in the Lilliput/750 group than in the Minimax group.

CONCLUSION: By using an adequate priming volume, the systemic inflammatory response is similar after use of the Dideco Lilliput 1 Oxygenator and the Medtronic Minimax Oxygenator. Tip-to-tip surface coating of the extracorporeal circulation with either heparin or phosphorylcholine seems to have similar biologic effects in neonates and infants undergoing cardiac surgery.

	Patients and methods

Top Abstract Patients and methods Results Discussion APPENDIX 1 References

Except for one patient, children undergoing the Norwood I procedure were excluded from the study because they took part in another investigation. The need for extracorporeal circulatory assist after the operation was a postoperative exclusion criterion. Demographic data of the children, the kind of procedure, and the percentage of cyanotic malformations are listed in Table 2.

ECC setup
The ECC circuit was an open system and consisted of a heparin-coated system in the first group of patients: a Minimax Plus CB 3381 oxygenator (Medtronic) with an uncoated hardshell reservoir, a coated CB1339 arterial filter (Medtronic, Düsseldorf, Germany), and heparin-coated polyvinylchloride tubing. In the other group of patients, a Lilliput D 902 oxygenator (Dideco-Sorin, Puchheim, Germany) was combined with a coated D 736 arterial filter and polyvinylchloride tubing, and the whole circuit was coated with phosphorylcholine.

With this setup, the Medtronic Minimax Oxygenator required a 750-mL priming volume, whereas a 450-mL priming volume was sufficient for the Dideco Lilliput 1 Oxygenator (Lilliput/450). To exclude the volume effect, we therefore formed another group of patients treated with the Dideco Lilliput 1 Oxygenator with a 750-mL priming volume (Lilliput/750). The composition of priming volumes is given in Table 3.

The cardioplegia lines were uncoated. Because crystalloid cardioplegia was given from the anesthesiologist's position, this line did not have contact with blood. Other material and methods that might affect SIR (aprotinin and modified ultrafiltration, as well as homograft material) were not used throughout the study.

Anesthesia and surgical procedures
Total intravenous anesthesia was introduced with sufentanil and pancuronium, sometimes aided by the application of isoflurane. Premedication (midazolam) was only given in children older than 6 months. Steroid pretreatment (1.5 mg/kg dexamethasone) was administered the evening before the operation and not during ECC.

After median sternotomy and hemithymectomy, the pericardium was opened, and heparin (300 U/kg body weight) was administered. Cannulation of the main systemic artery and the right atrium or the caval veins was performed, followed by induction of the ECC. Depending on the procedure, the children were either kept in moderate hypothermia or cooled down to deep hypothermia. The surgical procedure was carried out under low-flow perfusion to avoid long uninterrupted periods of total circulatory arrest. In cases with aortic crossclamping, St Thomas II cardioplegia was infused in an antegrade manner with a dose of 10 mL/kg body weight. A cardioplegia dose of 20 mL was repeated every 30 minutes.

None of the patients received aprotinin intraoperatively. Hemofiltration or ultrafiltration was not used routinely but rather in 1 or 2 patients in each group. The heparin effect was monitored throughout the procedure by using the activated clotting time with an ACT II device (Medtronic), maintaining the activated clotting time at greater than 400 seconds. Neutralization of heparin at the end of CPB was achieved with protamine sulfate (1:1 heparin dosage).

Depending on the individual cardiac performance, dopamine, adrenalin, or nitroprusside sodium was infused continuously before weaning from CPB, and phosphodiesterase inhibitors were given as a bolus.

Collection of blood samples
Blood samples (interleukin [IL] 6, tumor necrosis factor [TNF] , elastase, C3, free hemoglobin, hemoglobin, erythrocytes, leukocytes, thrombocytes, and C-reactive protein [CRP]) were taken before skin incision, after ECC induction, after protamine application, and 1, 4, 8, and 24 hours after skin closure. On the second, third, and fifth day after the operation, only levels of hemoglobin, erythrocytes, leukocytes, thrombocytes, and CRP were determined.

IL-6 was measured as a marker for white cell interaction and complement activation, neutrophil elastase and TNF- were measured as markers for activation of leukocytes, and complement C3 was measured as a marker for activation of both complement pathways. All samples were immediately centrifuged and either stored at –80°C or freshly analyzed. CRP and leukocyte counts were registered as markers for systemic inflammation, and free hemoglobin and total hemoglobin values were registered as markers for hemolysis by the ECC. Erythrocyte and thrombocyte counts were obtained to detect differences in blood dilution and cellular coagulation disorders. Samples for these values were directly analyzed in the hospital's laboratory by using routine methods.

Collection of clinical data
Seghaye and associates¹ defined multiple system organ failure (MSOF) as the acute simultaneous occurrence in the first postoperative week of the failure of at least 2 vital organs in addition to cardiac insufficiency, thrombocytopenia (<100,000/µL), and high fever (>39°C). For our study, thrombocyte counts, body temperature, diuresis, creatinine levels, peritoneal dialysis, prothrombin time, coma or seizure, and abdominal bleeding were documented. In addition, the durations of adrenalin support and ventilation were recorded. A capillary leak syndrome was defined as clinically detectable local or generalized edema.

Statistical analyses
Statistical analyses were performed with SPSS computer software. Depending on violations of normal distribution (Kolmogorov-Smirnov test), we described the data either by mean values with SDs or by median values with 25th and 75th percentiles. To detect differences between treatment groups, we performed t tests, Wilcoxon rank sum tests, Fisher exact tests, or ² tests adjusted with the Bonferroni correction for multiple testing. The relationship between the possible confounding variables of age and capillary leak, duration of catecholamine therapy, ventilation time, IL-6 value, and TNF- is expressed by the Spearman correlation coefficient. For all tests, a 2-tailed significance level of 5% was set.

	Results

Top Abstract Patients and methods Results Discussion APPENDIX 1 References

 
TNF-
Peak values were reached during the procedure (Lilliput/750, 60 ± 95 pg/mL; Lilliput/450, 20 ± 25 pg/mL; and Minimax, 35 ± 62 pg/mL), with a gentle decrease over the next 24 hours (Figure 1). Within the groups, there were major differences between the lowest and highest value at each measurement point, resulting in high SDs. Thus statistically significant differences could not be detected. However, the mean TNF- peak value in the Lilliput/750 group was higher than that in the Lilliput/450 group.

View larger version (17K): [in this window] [in a new window]   Figure 1. Peak values for TNF- during surgical intervention do not differ significantly between groups but are highest in the Lilliput/750 group. Preop, Preoperative; postop, postoperative.

View larger version (17K): [in this window] [in a new window]   Figure 2. IL-6 values during surgical intervention were insignificantly higher in the Lilliput/750 group.

Neutrophil elastase peaked at the end of the operation in the Lilliput/450 (305 ± 233.7 pg/mL) and Minimax (221.4 ± 105.2 pg/mL) groups, whereas its maximum in the Lilliput/750 group (261 ± 348.8 pg/mL) was reached only at 4 hours after the operation. In contrast to TNF- and IL-6, the highest mean values of elastase were detected in the Lilliput/450 group, which might represent a more intensive activation of neutrophils in the Lilliput/450 group.

Leukocytes and CRP
Leukocytes and CRP reacted with an increase during the first hours after the operation and peaked at 24 hours (Lilliput/750: leukocytes, 16.7 ± 6.5/nL; CRP, 6.4 ± 4.1 mg/dL; Lilliput/450: leukocytes, 14 ± 4.2/nL; CRP, 7.5 ± 5.2 mg/dL; Minimax: leukocytes, 13.8 ± 4.2/nL; CRP, 7.7 ± 3.1 mg/dL), without significant differences between the groups. CRP values decreased rapidly after this peak, and leukocyte values remained at a higher level, as before the operation.

Erythrocytes, thrombocytes, complement C3, and total hemoglobin
Because of dilution with onset of the ECC (Figure 3), low counts of erythrocytes, thrombocytes, complement C3, and total hemoglobin were seen. The parameters normalized under substitution at the end of the operation and remained stable until the fifth postoperative day. This is also shown in Figure 4, in which a 50% to 70% reduction of thrombocyte numbers during bypass is shown. This is reversed after bypass by thrombocyte transfusions during the first 4 hours.

View larger version (16K): [in this window] [in a new window]   Figure 3. Complement C3, hemoglobin, and erythrocyte values showed a similar decrease caused by dilution on ECC and normalized under substitution.

View larger version (26K): [in this window] [in a new window]   Figure 4. During bypass, a nearly 70% reduction of thrombocyte numbers occurs, which is reversed by transfusion during the first postoperative hours.

	Discussion

Top Abstract Patients and methods Results Discussion APPENDIX 1 References

The clinical results (Table 4) during this trial were satisfying. The mortality was 2.5% (one patient died from multiple organ failure after cavopulmonary anastomosis), and the incidence of clinically apparent MSOF, as defined by Seghaye and colleagues¹ was 5% (one was the patient who died subsequently, and another patient recovered fully). Compared with the high incidence of MSOF, reported by Seghaye and colleagues¹ as being as high as 27.5% with a noncoated CPB circuit, our results seem to be comparably good. The apparently high incidence of capillary leak syndromes is caused by the fact that for this study, every patient with the mention of edema (also only eyelid and face edema) was defined as having a capillary leak syndrome.

In our series of neonates and infants with a BSA of less than 0.36 m², these good results are achieved by means of a management that includes some factors diminishing the probability of SIR formation:

• Surface coating of ECC materials, such as oxygenators, filters, and tubing, reduces the SIR in pediatric patients, which has been proved especially for heparin^5-7 but also for phosphorylcholine.³ The reduction in SIR caused by surface coating is not only detectable on the basis of laboratory results like a lower cytokine release but also by clinical results like reduced respiratory index and body weight percent ratio⁶ and improved pulmonary and coagulation function.⁵ Other studies prove exactly the opposite: Horton and coworkers⁸ showed that heparin bonding in pediatric patients does not affect the IL-6 or IL-8 concentrations during and after CPB. In this study, however, heparin bonding was limited to the oxygenator only, which separates their methodology from our tip-to-tip coated systems and therefore might explain differences in the results. Defraigne and associates⁹ and Steinberg and coworkers¹⁰ showed in adults that TNF-, IL-6, IL-8, and elastase levels showed no significant differences irrespective of whether heparin coating was used. The adult patient is far less prone to SIR than the neonate, which makes the author's results difficult to compare with ours.
  
• Administration of a phosphodiesterase-inhibiting agent (milrinone) suppresses the cytokine production (IL-1 and IL-6) in adult patients by increasing cyclic adenosine monophosphate levels¹¹ while leaving the TNF- and IL-8 values unchanged. Looking at our patients, we could not find a significant difference in cytokine levels between the patients receiving milrinone and those without.
  
• Treatment with the nitric oxide donor sodium nitroprusside in adults decreases the cardiac production of TNF- and IL-6,¹² which could also be a beneficial effect in our pediatric patients.
  
• Corticosteroids reduce plasma levels of elastase and TNF- during and after CPB,¹³ the administration of methylprednisolone to the pump prime abrogates the patient's response to CPB,¹⁴ and steroid pretreatment reduces endotoxin release during bypass.¹⁵
  
• Centrifugal pumps cause greater complement and neutrophil activation during surgical intervention than roller pumps, with this effect ending soon after the procedure.¹⁶ Therefore the use of roller pumps might have contributed to a lower SIR in our patients.
  

One factor that cannot be avoided increases the probability of SIR formation: the transfusion of packed red cell units intraoperatively contributes to the inflammatory response by increasing the IL-6 levels after the operation.¹⁷ Because every patient in our study was treated with an ECC prime containing packed red cells and every patient received transfusions after the operation, it is likely that this fact contributed to an increase in IL-6 concentrations. Possibly the lower quantity of packed red cells in the Lilliput/450 group is one of the factors leading to improved results with the low-prime compared with the high-prime circuit. Interestingly, in spite of the uneven distribution of packed red cells in the priming (Table 3), in the Minimax group (300 mL of packed red cells) and the Lilliput/450 group (100 mL of packed red cells), the IL-6 course (Figure 2) was nearly identical.

The most severe limitations of this study are the uneven distribution of age and cyanosis in the 3 groups in spite of a prospective randomized design and the relatively small number of patients included in the study. However, post hoc statistical analysis showed no influence of age on the results, except for capillary leak syndrome. The development of a study design excluding cyanotic patients would only reflect half the truth about our clinical reality and lead to a further reduction of the patient numbers in the study.

Because of the young patient's individual variability, it would have been better to include 200 than 40 patients in such a study. Owing to limited financial and personal sources, it is not possible to produce such big numbers not only in our hospital but in most institutions.

We did not add a study arm with uncoated ECC tubing because we have used coated ECC equipment only since 1996 for pediatric and adult patients. Because there is evidence^3,5,6 that ECC circuits with surface coatings have several advantages over uncoated oxygenators and tubing, we did not find it acceptable to go a step backwards and use uncoated tubing again.

In conclusion, our results show no superiority of one coating (heparin, Medtronic Minimax) over the other (phosphorylcholine, Dideco Lilliput 1). By using the same priming volume, the SIR was more pronounced after use of the Dideco Lilliput 1 Oxygenator than after use of the Medtronic Minimax Oxygenator. Tip-to-tip surface coating of the ECC with either heparin or phosphorylcholine seems to have similar biologic effects in neonates and infants undergoing cardiac surgery.

	APPENDIX 1

Top Abstract Patients and methods Results Discussion APPENDIX 1 References

 

Spearman correlation coefficients of age and study results

Correlation with age (d) r Value P value Body weight (kg) 0.776 .000 Body surface area (m2) 0.824 .000 ECC time (min) –0.066 .700 Aortic clampingtime (min) –0.316 .054 Circulatory arrest time (min) –0.063 .703 IL-6 during bypass –0.156 .403 IL-6 1 h after the operation –0.142 .431 TNF- during bypass 0.183 .381 Adrenalin support (h) –0.396 .116 Ventilation (h) –0.215 .392

ECC, Extracorporeal circulation; IL, interleukin; TNF, tumor necrosisfactor.

	Acknowledgments

 
We acknowledge the assistance of P. Dütschke, MD, U. Bläse, ECCP, and the staff of the Pediatric Cardiology Intensive Care Unit in conducting this study.

	References

Top Abstract Patients and methods Results Discussion APPENDIX 1 References

 

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