Pediatric Cardiology

, Volume 40, Issue 4, pp 744–752 | Cite as

Analysis of Inflammatory Cytokines in Postoperative Fontan Pleural Drainage

  • Stephanie A. GoldsteinEmail author
  • Asaad G. Beshish
  • Lauren B. Bush
  • Ray E. Lowery
  • Joshua H. Wong
  • Kurt R. Schumacher
  • Nadine L. N. Halligan
  • Timothy T. Cornell
  • Albert P. Rocchini
Original Article


Prolonged pleural drainage is a common complication in patients after Fontan palliation and is associated with short- and long- term morbidities. Among many potential etiologies, prolonged drainage has an inflammatory component, but there are no descriptions of cytokines in Fontan pleural drainage to date. This study aimed to examine the inflammatory make-up of Fontan pleural drainage. This prospective age-range-matched cohort study recruited 25 patients undergoing Fontan procedure and 15 bi-ventricular patients undergoing cardiopulmonary bypass (CPB). Chest tube samples were taken on postoperative day (POD) 1–4, 7, and 10. Cytokines were measured using Bio-Plex Assays. Univariate comparisons were made in patient characteristics and cytokine levels. Median age was 3.7 y (IQR 2.8–3.9) for controls and 2.5 y (IQR 2.1–2.9) in Fontan patients (p = 0.02). Median drainage duration and daily volume was higher in Fontan patients (both p < 0.001). Inflammatory cytokines (IL-17A, IFN-y, MIP-1β, and TNF-α) were higher in Fontan patients than controls (all p < 0.02). There was an increase in pro-inflammatory cytokines (IL-8, MIP-1β, and TNF-α) from POD1 to the last chest tube day (LCD) in Fontan patients (all p < 0.0001) and a decrease in the anti-inflammatory cytokine IL-10 (p = 0.001). There was no difference in cytokine concentration from POD1 to LCD among controls. There was a significant association with the cytokine concentration of TNF-α on POD1 and duration of chest tube drainage (p < 0.05). Inflammatory cytokine levels in the pleural fluid of Fontan patients are higher compared to bi-ventricular controls and rise over time where controls do not. This suggests ongoing localized inflammation that is not a result of CPB alone and may be an important contributor to pleural drainage in patients after the Fontan procedure.


Fontan physiology Inflammation Postoperative Effusions 



The following people were paramount in the collection and storage of samples: Katherine Fatum RN BSN, Janine Stoscup RN BSN, Karianne Marchetti RN BSN, Katie Jarvis RN BSN, Holli Clewis RN BSN. Walker McHugh and Kevin Walker assisted with laboratory protocols.


Funding was provided by the Strecher award for fellowship research, Ann Arbor, MI.

Compliance with Ethical Standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical Approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.


  1. 1.
    Fontan F, Baudet E (1971) Surgical repair of tricuspid atresia. Thorax 26:240–248. CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Tweddell JS, Nersesian M, Mussatto KA et al (2009) Fontan palliation in the modern era: factors impacting mortality and morbidity. Ann Thorac Surg 88:1291–1299. CrossRefPubMedGoogle Scholar
  3. 3.
    Feinstein JA, Benson DW, Dubin AM et al (2012) Hypoplastic left heart syndrome: current considerations and expectations. J Am Coll Cardiol 59:S1–S42. CrossRefGoogle Scholar
  4. 4.
    Hirsch JC, Goldberg C, Bove EL et al (2008) Fontan operation in the current era: a 15-year single institution experience. Ann Surg 248:402–410. CrossRefPubMedGoogle Scholar
  5. 5.
    Rogers LS, Glatz AC, Ravishankar C et al (2012) 18 years of the Fontan operation at a single institution: Results from 771 consecutive patients. J Am Coll Cardiol 60:1018–1025. CrossRefPubMedGoogle Scholar
  6. 6.
    Schumacher KR, Singh TP, Kuebler J et al (2014) Risk factors and outcome of Fontan-associated plastic bronchitis: a case-control study. J Am Heart Assoc 3(2):e000865. CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Savla JJ, Itkin M, Rossano JW, Dori Y (2017) Post-operative chylothorax in patients with congenital heart disease. J Am Coll Cardiol 69(19):2410–2422CrossRefPubMedGoogle Scholar
  8. 8.
    Cava JR, Bevandic SM, Steltzer MM, Tweddell JS (2005) A medical strategy to reduce persistent chest tube drainage after the fontan operation. Am J Cardiol 96:130–133. CrossRefPubMedGoogle Scholar
  9. 9.
    Chan EH, Russell JL, Williams WG et al (2005) Postoperative chylothorax after cardiothoracic surgery in children. Ann Thorac Surg 80:1864–1870. CrossRefPubMedGoogle Scholar
  10. 10.
    Mainwaring RD, Lamberti JJ, Hugli TE (1998) Complement activation and cytokine generation after modified fontan procedure. Ann Thorac Surg 65:1715–1720. CrossRefPubMedGoogle Scholar
  11. 11.
    Kawahira Y, Uemura H, Yagihara T (2006) Impact of the off-pump Fontan procedure on complement activation and cytokine generation. Ann Thorac Surg 81:685–689. CrossRefPubMedGoogle Scholar
  12. 12.
    Wan S, Leclerc JL, Vincent JL (1997) Inflammatory response to cardiopulmonary bypass: mechanisms involved and possible therapeutic strategies. Chest. CrossRefPubMedGoogle Scholar
  13. 13.
    Durandy Y (2014) Minimizing systemic inflammation during cardiopulmonary bypass in the pediatric population. Artifi Organs 38(1):11–18CrossRefGoogle Scholar
  14. 14.
    Van Der Heide HJL, Van Der Kraan PM, Rijnberg WJ et al (2010) Elevated levels of numerous cytokines in drainage fluid after primary total hip arthroplasty. Int Orthop 34:1099–1102. CrossRefPubMedGoogle Scholar
  15. 15.
    Weissflog D, Kroegel C, Luttmann W et al (1999) Leukocyte infiltration and secretion of cytokines in pleural drainage fluid after thoracic surgery: impaired cytokine response in malignancy and postoperative complications. Chest 115:1604–1610. CrossRefPubMedGoogle Scholar
  16. 16.
    Houser B (2012) Bio-Rad’s Bio-Plex® suspension array system, xMAP technology overview. Arch Physiol Biochem 118:192–196. CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Akdis M, Burgler S, Crameri R et al (2011) Interleukins, from 1 to 37, and interferon-γ: receptors, functions, and roles in diseases. J Allergy Clin Immunol 127:701–721CrossRefPubMedGoogle Scholar
  18. 18.
    Gaies MG, Gurney JG, Yen AH et al (2010) Vasoactive-inotropic score as a predictor of morbidity and mortality in infants after cardiopulmonary bypass. Pediatr Crit Care Med 11:234–238. CrossRefPubMedGoogle Scholar
  19. 19.
    Durairaj M, Sharma R, Choudhary SK et al (2002) Diaphragmatic fenestration for resistant pleural effusions after univentricular repair. Ann Thorac Surg 74:931–932. CrossRefPubMedGoogle Scholar
  20. 20.
    François K, Bové T, De Groote K et al (2009) Pleural effusions, water balance mediators and the influence of lisinopril after completion Fontan procedures. Eur J Cardio-thorac Surg 36:57–62. CrossRefGoogle Scholar
  21. 21.
    Sherry B, Tekamp-Olson P, Gallegos C et al (1988) Resolution of the two components of macrophage inflammatory protein 1, and cloning and characterization of one of those components, macrophage inflammatory protein 1 beta. J Exp Med 168:2251–2259. CrossRefPubMedGoogle Scholar
  22. 22.
    Idriss HT, Naismith JH (2000) TNF alpha and the TNF receptor superfamily: structure-function relationship(s). Microsc Res Tech 50:184–195.;2-H CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Stephanie A. Goldstein
    • 1
    Email author
  • Asaad G. Beshish
    • 2
  • Lauren B. Bush
    • 1
  • Ray E. Lowery
    • 1
  • Joshua H. Wong
    • 3
  • Kurt R. Schumacher
    • 1
  • Nadine L. N. Halligan
    • 1
  • Timothy T. Cornell
    • 2
  • Albert P. Rocchini
    • 1
  1. 1.University of Michigan Congenital Heart CenterAnn ArborUSA
  2. 2.Lucile Packard Children’s HospitalPalo AltoUSA
  3. 3.Advocate Children’s HospitalOak LawnUSA

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