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Ann Thorac Surg 1998;65:1715-1720
© 1998 The Society of Thoracic Surgeons

Original articles: cardiovascular

Complement Activation and Cytokine Generation After Modified Fontan Procedure

Richard D. Mainwaring, MDa, John J. Lamberti, MDa, Tony E. Hugli, PhDb

a Cardiac Institute, Children’s Hospital-San Diego, San Diego, California, USA
b Scripps Research Institute, San Diego, California, USA

Accepted for publication November 5, 1997.

Address reprint requests to Dr Mainwaring, Nemours Cardiac Center, A.I. Dupont Hospital for Children, PO Box 269, 1600 Rockland Rd, Wilmington, DE 19899


   Abstract
Top
 Abstract
Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
 References
 
Background. The modified Fontan procedure separates the systemic and pulmonary circulations in patients born with a functional single ventricle. Delayed recovery is frequently observed after this procedure. It was our hypothesis that complement activation or cytokine generation may contribute to the pathophysiology of this problem.

Methods. We measured activated complement C3, thromboxane B2, interleukin-6, and tumor necrosis factor-{alpha} levels by immunoassay in 16 patients undergoing Fontan procedure. Patient plasma samples were obtained preoperatively, on initiation of cardiopulmonary bypass, after administration of protamine, and 1, 4, 8, and 24 hours postoperatively.

Results. There was no early or late mortality in this cohort of patients. Low cardiac output developed in 3 of 16 patients, and pleural effusions developed in 5. The median length of hospital stay was 9 days. Activated complement C3 levels increased from a baseline of 1,486 ± 564 to 4,600 ± 454 ng/mL after cardiopulmonary bypass and administration of protamine, and returned to baseline by 24 hours. The level of interleukin-6 increased from 42 ± 32 to 176 ± 22 pg/mL and at 24 hours remained elevated at 71 ± 15 pg/mL. Neither thromboxane B2 nor tumor necrosis factor-{alpha} levels increased significantly.

Conclusions. The data demonstrate threefold to fourfold increases in activated complement C3 and interleukin-6, indicating that both humoral and cellular systems are affected. It is our conclusion that complement and cytokine activation may contribute to the delayed recovery observed after Fontan procedure.


   Introduction
Top
 Abstract
 Introduction
Material and methods
 Results
 Comment
 Acknowledgments
 References
 
The modified Fontan procedure is performed to separate the systemic and pulmonary circulations in patients born with a functional single ventricle. Delayed recovery is frequently observed after this operation, usually as a sequel to low cardiac output. The cause of low cardiac output after the Fontan procedure is multifactorial, potentially including such factors as mechanical obstruction, inadequate myocardial protection, alterations in systemic and pulmonary vascular resistances, decreased diastolic compliance of the ventricle, and endocrinologic dysfunction [1–3]. Low cardiac output remains the most important contributor to the morbidity and mortality observed after this procedure.

The process of cardiopulmonary bypass results in a systemic inflammatory response that has been well characterized in adults and has been implicated in development of postoperative organ dysfunction [4, 5]. This response is characterized by the production of bioactive complement fragments [6, 7] and release of cytokines [8, 9]. These vasoactive substances can mediate decreases in cardiac, pulmonary, and renal function and are also responsible for increased vascular permeability, fever, and leukocytosis. In individual cases, this response may overwhelm the host and result in multisystem organ failure. Thus, the process of using cardiopulmonary bypass has the undesired effect of stimulating an inflammatory response that may jeopardize the outcome of the operation.

In view of the well-recognized relationship between complement activation and cytokine production in the development of multisystem organ failure, the present study was performed to evaluate the inflammatory response after the Fontan procedure. Our hypothesis was that complement activation and cytokine generation may contribute to the delayed recovery observed after this congenital heart operation.


   Material and methods
Top
 Abstract
 Introduction
 Material and methods
Results
 Comment
 Acknowledgments
 References
 
Sixteen children were enrolled in this study. Ages, weights, and diagnoses are listed in Table 1. There were 10 boys and 6 girls. All 16 patients had undergone a previous hemi-Fontan procedure. The hemi-Fontan was performed at a median age of 6 months, and the median interval between hemi-Fontan and completion Fontan was 14 months. Permission for enrollment in this study was granted by the parents. The study protocol was approved by the hospital’s institutional review board. All subjects completed the protocol.


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  		Table 1. Patient Characteristics

 
Venous blood samples (4 mL) were obtained from the patients at seven time points: preoperatively, 10 minutes after institution of cardiopulmonary bypass, 10 minutes after administration of protamine, and at 1, 4, 8, and 24 hours postoperatively (timed after admission to the intensive care unit). Each of these seven samples was drawn into a tube containing ethylenediamine tetraacetic acid. The plasma fraction was then separated and stored at -70°C for subsequent quantitative analysis.

Anesthetic technique
On the morning of the operation, the patients were administered a premedication of fentanyl (2 µg/kg), droperidol (0.1 mg/kg), and glycopyrrolate (0.5 µg/kg) given intramuscularly. Once in the operating room, the patients were given ketamine (5 to 10 mg/kg), and intravenous access was obtained. Lactated Ringer’s solution (10 to 20 mL/kg) was given to maintain normal vital signs for the age and weight of the patient. Vecuronium (0.2 mg/kg) was used as a muscle relaxant. The patients were intubated and ventilated, and additional venous and arterial access were obtained. Fentanyl (50 µg/kg intravenously) was administered at the beginning of the procedure, and additional fentanyl and vecuronium were given as indicated during the procedure.

Cardiopulmonary bypass technique
Patients underwent median sternotomy, heparinization (300 U/kg), and bicaval venous cannulation. Moderate or deep hypothermia was used in conjunction with multidose blood cardioplegia for myocardial protection. A Cobe heart-lung machine (Cobe Laboratories, Arvada, CO) and Terumo membrane oxygenator (Terumo model 320; Terumo Corp, Tokyo, Japan) were used for perfusion. This oxygenator circuit has a prime volume of 1,200 mL. The prime solution contained Normosol (Abbott Laboratories, Abbott Park, IL), 5% albumin, adult packed red blood cells, and prednisolone (30 mg/kg).

Quantitative analysis
Plasma samples were analyzed at The Scripps Research Institute, La Jolla, California. Activated human complement C3 (C3a) was measured by radioimmunoassay kits obtained from Amersham International (Arlington Heights, IL) with an interassay coefficient of variation (CV) of less than or equal to 16.5% [10]. Thromboxane B2 was measured by enzyme immunoassay kits obtained from Cayman Chemical Co. (Ann Arbor, MI) with an interassay CV of less than 10% [11]. Interleukin-6 (IL-6) was measured by enzyme immunoassay kits obtained from Immunotech (Westbrook, ME) with an interassay CV of less than 14% [12]. Tumor necrosis factor-{alpha} (TNF-{alpha}) was measured by enzyme immunoassay kits from Immunotech with an interassay CV of less than 12% [13].

Statistical analysis
Results of the pooled data (n = 16) are expressed as the mean ± the standard error of the mean. The intraoperative and postoperative assay results were compared with the preoperative results using Wilcoxon signed rank test. A p value of less than 0.05 was considered significant. Results of patients with (n = 3) and without (n = 13) low cardiac output are expressed as median values without statistical comparison of the two groups.


   Results
Top
 Abstract
 Introduction
 Material and methods
 Results
Comment
 Acknowledgments
 References
 
Sixteen patients underwent completion of their Fontan without operative mortality. The cardiopulmonary bypass and surgical data for these 16 operations are shown in Table 2. On the morning after surgery, the average systemic blood pressure was 105 ± 7 and 56 ± 6 mm Hg (systolic and diastolic). The mean pulmonary artery pressure was 14 ± 1 mm Hg and the mean atrial pressure was 5 ± 1 mm Hg. Postoperatively, 3 patients had signs and symptoms of low cardiac output. Five patients had pleural effusions, as defined by the need for chest tube drainage of 1 week or longer duration. The median length of hospital stay was 9 days (range 6 to 34 days). All 16 patients remain alive and well with an average follow-up of 20 months.


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  		Table 2. Cardiopulmonary Bypass and Surgical Data

 
The results of the IL-6 assays are summarized in Figure 1. Interleukin-6 levels were relatively low preoperatively and remained unchanged upon institution of cardiopulmonary bypass. However, after the conclusion of bypass and administration of protamine, IL-6 levels were increased by more than threefold. Interleukin-6 levels peaked at 1 hour postoperatively, and then began to diminish, so that by 24 hours the levels were less than twofold increased as compared with the baseline levels.



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  		Fig 1. Changes in interleukin-6 (IL-6) levels in 16 patients undergoing modified Fontan procedure. (CPB = cardiopulmonary bypass; Pre-Op = preoperative; PROT = protamine.)

 
The data for C3a are summarized in Figure 2. Levels of C3a increased by more than threefold at the conclusion of cardiopulmonary bypass, and remained elevated at 1 and 4 hours postoperatively. However, the 8- and 24-hour levels were not statistically different from the preoperative value.



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  		Fig 2. Changes in activated complement C3 (C3a) levels in 16 patients undergoing modified Fontan procedure. (CPB = cardiopulmonary bypass; Pre-Op = preoperative; PROT = protamine.)

 
Thromboxane B2 data are summarized in Figure 3. These levels remained unchanged throughout the study.



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  		Fig 3. Changes in thromboxane B2 (TxB2) in 16 patients undergoing modified Fontan procedure. (CPB = cardiopulmonary bypass; Pre-Op = preoperative; PROT = protamine.)

 
Tumor necrosis factor-{alpha} data are summarized in Figure 4. Tumor necrosis factor-{alpha} decreased on initiation of cardiopulmonary bypass, but had returned to preoperative levels at the conclusion of bypass. Tumor necrosis factor-{alpha} was also found to be decreased at 4, 8, and 24 hours postoperatively.



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  		Fig 4. Changes in tumor necrosis factor (TNF) in 16 patients undergoing modified Fontan procedure. (CPB = cardiopulmonary bypass; Pre-Op = preoperative; PROT = protamine.)

 

   Comment
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
Acknowledgments
 References
 
The present study was performed to assess the complement, prostanoid, and cytokine response after the modified Fontan procedure. Activated complement C3, thromboxane B2, IL-6, and TNF-{alpha} were evaluated. Activated C3 and IL-6 increased threefold to fourfold after bypass as compared with the preoperative values, indicating that both humoral and cellular systems are affected. There were no significant increases in either thromboxane B2 or TNF-{alpha}. These results indicate a pronounced inflammatory response followed by rapid resolution in patients undergoing the modified Fontan procedure.

The four mediators selected for measurement in this study were chosen to monitor both humoral and cellular activation events during the Fontan procedure. Activated C3 levels reflect the extent of complement activation and indicate that C5a, a potent proinflammatory factor, has been generated. The IL-6 levels reflect potential direct activation of monocytes or macrophages and stimulation of the cellular acute phase response, as well as monitoring generation of one of a class of proinflammatory cytokines. The TNF-{alpha} measurement provides data on another potent inflammatory cytokine that also stimulates cell activation and the acute phase response, but in addition correlates with nitric oxide production from monocytes or macrophages [14].

The coproduction of nitric oxide during TNF-{alpha} release could exert a major influence on the hemodynamics and vasculature of the patient [14]. We monitored generation of cyclooxygenase products from mobilized arachidonate by measuring thromboxane B2 levels (a stable form of thromboxane A2, a potent vasoactive prostanoid). Together, these measurements provide a profile for major classes of circulating proinflammatory mediators and indicate possible factors exerting significant pathophysiologic effects in these patients during treatment.

Three of the 16 patients had low cardiac output. These patients accounted for the three longest lengths of stay in hospital and for 2 of the 5 patients who had pleural effusions. Analysis of the complement and cytokine response in these 3 patients revealed higher C3a and IL-6 levels both early postoperatively and at 24 hours compared with the remainder of the cohort (Fig 5). It is possible that a larger number of patients with low cardiac output would have proven that patients with low cardiac output have an exaggerated complement and cytokine response.



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  		Fig 5. Complement, prostanoid, and cytokine levels in patients with (black circles) and without (white circles) low cardiac output. Data shown are the median values of 3 patients with cardiac output and 13 without. (CPB = cardiopulmonary bypass; Pre-Op = preoperative; PROT = protamine.)

 
A limited number of studies have evaluated complement and cytokine levels in children undergoing cardiopulmonary bypass. These studies generally have focused on patients having two-ventricle repairs, in contrast to our study, which focused on patients with a functional single ventricle. Previous studies also showed complement activation, with similar peak values and duration as found in our study [15, 16, 17, 18]. Interleukin-6, IL-8, and IL-10 have also been shown to increase in children undergoing cardiopulmonary bypass, with a time course similar to that which we found for IL-6 [18–21]. Contradictory results have been previously reported for TNF-{alpha}, with some studies showing increased levels and others demonstrating no change [19–21]. We did not find an increase in TNF-{alpha}, although this was in part caused by slightly elevated TNF-{alpha} levels preoperatively. We also did not observe an increase in the arachidonate derivative thromboxane B2. A comparison of our results in patients undergoing the Fontan procedure with previous reports in children undergoing other types of open heart operations suggests that the complement and cytokine responses are similar.

We have previously shown that the euthyroid sick syndrome develops in children undergoing the modified Fontan procedure [3]; this syndrome is characterized by low free triiodothyronine levels despite relatively normal thyroid-stimulating hormone and L-thyroxine levels. Free triiodothyronine accounts for nearly all of the biologic activity of thyroid hormone and has important effects on cardiac performance, including increased heart rate and contractility and decreased systemic vascular resistance. Changes in free triiodothyronine levels result in a dose-dependent increase (or decrease) in cardiac output. Experimental data suggest that cytokines may play a role in the development of the euthyroid sick syndrome. Both IL-6 and TNF-{alpha} have been shown to induce the euthyroid sick syndrome in animal studies [22–24]. We speculate that complement and cytokine generation may mediate more lasting effects through their influence on the thyroid hormone system.

In conclusion, this study has shown significant increases in C3a and IL-6 early postoperatively in children undergoing the modified Fontan procedure. These changes were short-lived, having largely resolved by 24 hours. These results suggest that activation of complement and release of cytokines may contribute to the slow recovery seen after the modified Fontan procedure.


   Acknowledgments
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
References
 
We thank Maureen Finegan for her help in coordinating laboratory studies and Marleen Kawahara for her technical assistance with radioimmunoassays. This study was funded through the generous donation of Ms Sandra Ackerman.


   References
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
 References
 

  1. Mainwaring R.D., Lamberti J.J., Moore J.W., Billman G.F., Nelson J.C. A comparison of the hormonal response after bidirectional Glenn and Fontan procedures. Ann Thorac Surg 1994;57:59-64.[Abstract]
  2. Mainwaring R.D., Lamberti J.J., Carter T.L., Moore J.W., Nelson J.C. Renin, angiotensin II, and the development of effusions following bidirectional Glenn and Fontan procedures. J Card Surg 1995;10:111-118.[Medline]
  3. Mainwaring R.D., Lamberti J.J., Carter T.L., Nelson J.C. Reduction in triiodothyronine levels following modified Fontan procedure. J Card Surg 1994;9:322-331.[Medline]
  4. Edmunds L.H., Jr Why cardiopulmonary bypass makes patients sick: strategies to control the blood–synthetic surface interface. Adv Card Surg 1995;6:131-167.[Medline]
  5. Cremer J., Martin M., Redl H., et al. Systemic inflammatory response syndrome after cardiac operations. Ann Thorac Surg 1996;61:1714-1720.[Abstract/Free Full Text]
  6. Kirklin J.K., Westaby S., Blackstone E.H., Kirklin J.W., Chenoweth D.E., Pacifico A.D. Complement and the damaging effects of cardiopulmonary bypass. J Thorac Cardiovasc Surg 1983;86:845-857.[Abstract]
  7. Moat N.E., Shore D.F., Evans T.W. Organ dysfunction and cardiopulmonary bypass: the role of complement and complement regulatory proteins. Eur J Cardiothorac Surg 1993;7:563-573.[Abstract]
  8. Steinberg J.B., Kapelanski D.P., Olson J.D., Weiler J.M. Cytokine and complement levels in patients undergoing cardiopulmonary bypass. J Thorac Cardiovasc Surg 1993;106:1008-1016.[Abstract]
  9. Butler J., Parker D., Pillai R., Westaby S., Schale D.J., Rocker G.M. Effect of cardiopulmonary bypass on systemic release of neutrophil elastase and tumor necrosis factor. J Thorac Cardiovasc Surg 1993;105:25-30.[Abstract]
  10. Wagner J.L., Hugli T.E. Radioimmunoassay of anaphylatoxins: a sensitive method for determining complement activation products in biological fluids. Ann Biochem 1984;136:75-88.
  11. Pradelles P., Grassi J., Maclouf J. Enzyme immunoassays of eicosanoids using acetylcholine esterase as label: an alternative to radioimmunoassay. Ann Chem 1985;57:1170-1173.
  12. Antoine C., Lellouche J.P., Maclouf J., et al. Development of enzyme immunoassays for leukotrienes using acetylcholinesterase. Biochem Biophy Acta 1991;1075:162-168.
  13. Engvall E., Perlmann P. Enzyme-linked immunoabsorbent assay (ELISA). J Immunol 1972;109:129-135.[Abstract/Free Full Text]
  14. Lander H.M., Sehajpal P., Levine D.M., Novogrodski A. Activation of human peripheral blood mononuclear cells by nitric oxide-generating compounds. J Immunol 1993;150:1509-1516.[Abstract]
  15. Ouaaz F., Sola B., Issaly D., et al. Growth arrest and terminal differentiation of leukemic myelomonocytic cells induced through ligation of surface CD23 antigen. Blood 1994;84:3095-3104.[Abstract/Free Full Text]
  16. Dugas B., Mossalayi M.D., Damais C., Kolb J.P. Nitric oxide production by human monocytes: evidence for a role of CD23. Immunol Today 1995;16:574-580.[Medline]
  17. Seghaye M.C., Duchateau J., Grabitz R.G., et al. Complement activation during cardiopulmonary bypass in infants and children. J Thorac Cardiovasc Surg 1993;106:978-987.[Abstract]
  18. Butler J., Pathi V.L., Paton R.D., et al. Acute-phase responses to cardiopulmonary bypass in children weighing less than 10 kg. Ann Thorac Surg 1996;62:538-542.[Abstract/Free Full Text]
  19. Behr D., Hervann A., Pouard P., et al. Interleukin-6 and C reactive protein during pediatric cardiopulmonary bypass. J Clin Chem 1995;41:467-469.
  20. Finn A., Naik S., Klein N., Levinsky R.J., Strobel S., Elliott M. Interleukin-8 release and neutrophil degranulation after pediatric cardiopulmonary bypass. J Thorac Cardiovasc Surg 1993;105:234-241.[Abstract]
  21. Seghaye M.-C., Duchateau J., Bruniaux J., et al. Interleukin-10 release related to cardiopulmonary bypass in infants undergoing cardiac operations. J Cardiovasc Surg 1996;111:545-553.
  22. Van der Poll T., Romijn J.A., Wiersinga W.M., Sauerwein H.P. Tumor necrosis factor: a putative mediator of the sick euthyroid syndrome in man. J Clin Endocrinol Metab 1990;71:1567-1572.[Abstract/Free Full Text]
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