Advertisement

Pediatric Cardiology

, Volume 40, Issue 3, pp 546–553 | Cite as

A Novel Brain Injury Biomarker Correlates with Cyanosis in Infants with Congenital Heart Disease

  • Lindsey McPhillipsEmail author
  • Dipak Kholwadwala
  • Cristina P. Sison
  • Dorota Gruber
  • Kaie OjamaaEmail author
Original Article

Abstract

Cyanotic heart lesions are a complex subset of congenital heart disease (CHD) in which patients are desaturated until surgical repair or palliation. We hypothesized that a direct relationship would exist between degree of desaturation and presence of systemic inflammation and brain injury in unrepaired patients less than 1 year of age. The pre-operative desaturation with augmented systemic inflammation would predict a more complex post-operative course. Fifty patients with CHD were enrolled in this study and classified as cyanotic (O2 ≤ 90%) or acyanotic (O2 > 90%) based on SpO2. Serum inflammatory mediators measured included interleukins (IL)-6, IL-8, IL-12p70, IL-10, IL-1β, tumor necrosis factor (TNF)-α, interferon (INF)-γ; macrophage inhibitory factor (MIF) and a novel brain biomarker, phosphorylated neurofilament heavy subunit (pNF-H). Twenty-two cyanotic and 28 acyanotic subjects were enrolled with SpO2 of 78 ± 18% and 98 ± 2% (p < 0.001), respectively, and mean age of 72 days (range 2–303) and 102 days (range 1–274), respectively. Cyanotic vs acyanotic subjects had elevated serum IL-6 (6.6 ± 7.6 vs 2.9 ± 2.9 pg/ml, p = 0.019) and pNF-H (222 ± 637 vs 57 ± 121 pg/ml, p = 0.046), and both biomarkers correlated with degree of desaturation (Spearman rank-order correlation ρ = − 0.30, p = 0.037 and ρ = − 0.29 p = 0.049, respectively). Post-operative inotrope scores at 24 h and duration of mechanical ventilation correlated inversely with pre-operative oxygen saturation (ρ = − 0.380, p = 0.014 and ρ = − 0.362, p = 0.020, respectively). The degree of pre-operative desaturation correlated with a more complicated post-operative course supporting the need for advanced peri-operative therapy in this population.

Keywords

Congenital heart disease Systemic inflammation Brain injury Cytokines Neurofilament Bypass surgery 

Notes

Funding

This study was not funded.

Compliance with Ethical Standards

Conflict of interest

None of the authors have any 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.

Informed Consent

Informed consent was obtained from all individual participants included in the study.

References

  1. 1.
    Hoffman JIE, Kaplan S (2002) The incidence of congenital heart disease. J Am Coll Cardiol 39(12):1890–1900CrossRefGoogle Scholar
  2. 2.
    Allen HD, Driscoll DJ, Shaddy RE, Feltes TF (2013) Moss & Adams’ Heart disease in infants, children, and adolescents: including the fetus and young adult. Lippincott Williams & Wilkins, PhiladelphiaGoogle Scholar
  3. 3.
    Theodore AC (2016) Oxygenation and mechanisms of hypoxemia. http://www.uptodate.com/home. Accessed 29 May 2016
  4. 4.
    Hovels-Gurich HH, Schumacher K, Vazquez-Jimenez JF, Qing M, Huffmeier U, Buding B, Messmer BJ, von Bernuth G, Seghaye MC (2002) Cytokine balance in infants undergoing cardiac operation. Ann Thorac Surg 73(2):601–608CrossRefGoogle Scholar
  5. 5.
    Qing M, Schumacher K, Heise R, Woltje M, Vazquez-Jimenez JF, Richter T, Arranda-Carrero M, Hess J, von Bernuth G, Seghaye MC (2003) Intramyocardial synthesis of pro- and anti-inflammatory cytokines in infants with congenital cardiac defects. J Am Coll Cardiol 41(12):2266–2274CrossRefGoogle Scholar
  6. 6.
    Madhok AB, Ojamaa K, Haridas V, Parnell VA, Pahwa S, Chowdhury D (2006) Cytokine response in children undergoing surgery for congenital heart disease. Pediatr Cardiol 27:408–413CrossRefGoogle Scholar
  7. 7.
    Pironkova RP, Giamelli J, Seiden H, Parnell VA, Gruber D, Sison CP, Kowal C, Ojamaa K (2017) Brain injury with systemic inflammation in newborns with congenital heart disease undergoing heart surgery. Exp Ther Med 14(1):228–238CrossRefGoogle Scholar
  8. 8.
    Allan CK, Newburger JW, McGrath E, Elder J, Psoinos C, Laussen PC, del Nido PJ, Wypij D, McGowan FX Jr (2010) The relationship between inflammatory activation and clinical outcome after infant cardiopulmonary bypass. Anesth Analg 111(5):1244–1251CrossRefGoogle Scholar
  9. 9.
    Mahle WT, Matthews E, Kanter KR, Kogon BE, Hamrick SE, Strickland MJ (2014) Inflammatory response after neonatal cardiac surgery and its relationship to clinical outcomes. Ann Thorac Surg 97(3):950–956CrossRefGoogle Scholar
  10. 10.
    Kozik DJ, Tweddell JS (2006) Characterizing the inflammatory response to cardiopulmonary bypass in children. Ann Thorac Surg 81(6):S2347–S2354CrossRefGoogle Scholar
  11. 11.
    Marino BS, Lipkin PH, Newburger JW, Peacock G, Gerdes M, Gaynor CS, Johnson WH Jr, Li J, Smith SE, Bellinger DC, Mahle WT (2012) American Heart Association Congenital Heart Defects Committee, Council on Cardiovascular Disease in the Young, Council on Cardiovascular Nursing and Stroke Council, Neurodevelopmental outcomes in children with congenital heart disease; evaluation and management: a scientific statement from the American Heart Association. Circulation 126:1143–1172CrossRefGoogle Scholar
  12. 12.
    Wernovsky G, Wypij D, Jonas RA, Mayer JE Jr, Hanley FL, Hickey PR, Walsh AZ, Chang AC, Castaneda AR, Newburger JW (1995) Postoperative course and hemodynamic profile after the arterial switch operation in neonates and infants. A comparison of low-flow cardiopulmonary bypass and circulatory arrest. Circulation 92(8):2226–2235CrossRefGoogle Scholar
  13. 13.
    Diesner SC, Forster-Waldi E, Olivera A, Pollak A, Jensen-Jarolim E, Untersmayr E (2012) Perspectives on immunomodulation early in life. Pediatr Allergy Immunol  https://doi.org/10.1111/j.1399-3038.2011.01259 Google Scholar
  14. 14.
    Mayo Medical Laboratories. Mayo Foundation for Medical Education and Research. 1995–2018. https://www.mayomedicallaboratories.com/index.html Accessed 24 Sept 2018
  15. 15.
    Grieb G, Merk M, Bernhagen J, Bucala R (2010) Macrophage migration inhibitory factor (MIF): a promising biomarker. Drug News Perspect 23(4):257–264CrossRefGoogle Scholar
  16. 16.
    Gabay C (2006) Interleukin-6 and chronic inflammation. Arthritis Res Thery 8(Suppl 2):S3CrossRefGoogle Scholar
  17. 17.
    Ali MH, Schlidt SA, Chandel NS, Hynes KL, Schumacker PT, Gewertz BL (1999) Endothelial permeability and IL-6 production during hypoxia: role of ROS in signal transduction. Am J Physiol-Lung Cell Mol Physiol 277(5):1057–1065CrossRefGoogle Scholar
  18. 18.
    Klausen T, Olsen NV, Poulsen TD, Richalet JP, Pederson BK (1997) Hypoxemia increases serum interleukin-6 in humans. Eur J Appl Physiol 76:480–482CrossRefGoogle Scholar
  19. 19.
    Matsui H, Ihara Y, Fujio Y, Kunisada K, Akira S, Kishimoto T, Yamauchi-Takihara K (1999) Induction of interleukin (IL)-6 by hypoxia is mediated by nuclear factor (NF)-κB and NF-IL6 in cardiac myocytes. Cardiovasc Res 42:104–112CrossRefGoogle Scholar
  20. 20.
    Vlahopoulos S, Boldlogh I, Casola A, Brasier AR (1999) Nuclear factor-κB–dependent induction of interleukin-8 gene expression by tumor necrosis factor α: evidence for an antioxidant sensitive activating pathway distinct from nuclear translocation. Blood 94(6):1878–1889Google Scholar
  21. 21.
    Xing Z, Gauldie J, Cox G, Baumann H, Jordana M, Lei XF, Achong MK (1998) IL-6 is an antiinflammatory cytokine required for controlling local or systemic acute inflammatory responses. J Clin Invest 101(2):311–320CrossRefGoogle Scholar
  22. 22.
    Gabay C, Smith MF, Eidlen D, Arend WP (1997) Interleukin 1 receptor antagonist (IL-1Ra) is an acute-phase protein. J Clin Invest 99(12):2930–2940CrossRefGoogle Scholar
  23. 23.
    Güvener M, Korun O, Demirtürk OS (2015) Risk factors for systemic inflammatory response after congenital cardiac surgery. J Card Surg 30:92–96CrossRefGoogle Scholar
  24. 24.
    Hayakawa K, Okazaki R, Ishii K, Ueno T, Izawa N, Tanaka Y, Toyooka S, Matsuoka N, Morioka K, Ohori Y, Nakamura K, Akai M, Tobimatsu Y, Hamabe Y, Ogata T (2012) Phosphorylated neurofilament subunit NF-H as a biomarker for evaluating the severity of spinal cord injury patients, a pilot study. Spinal Cord 50:493–496CrossRefGoogle Scholar
  25. 25.
    Singh A, Kumar V, Ali S, Mahdi AA, Srivastava RN (2017) Phosphorylated neurofilament heavy: a potential blood biomarker to evaluate the severity of acute spinal cord injuries in adults. Int J Crit Illness Injury Sci 7(4):212–217CrossRefGoogle Scholar
  26. 26.
    Douglas-Escobar M, Yang C, Bennet J, Shuster J, Theriaque D, Leibovici A, Kays D, Zheng T, Rossignol C, Shaw G, Weiss M (2010) A pilot study of novel biomarkers in neonates with hypoxic-ischemic encephalopathy. Pediatr Res 68(6):531–536CrossRefGoogle Scholar
  27. 27.
    Shedeed SA, Elfaytouri E (2011) Brain maturity and brain injury in newborns with cyanotic congenital heart disease. Pediatr Cardiol 32:47CrossRefGoogle Scholar
  28. 28.
    Kleiner G, Marcuzzi A, Zanin V, Monasta L, Zauli G (2013) Cytokine levels in the serum of healthy subjects. Mediat Inflam 2013 (2013)Google Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Division of Pediatric Cardiology, Department of PediatricsCohen Children’s Medical Center of New York at Northwell HealthNew Hyde ParkUSA
  2. 2.Barbara and Donald Zucker School of Medicine at Hofstra/NorthwellHempsteadUSA
  3. 3.Biostatistics UnitThe Feinstein Institute for Medical Research, Northwell HealthManhassetUSA
  4. 4.Department of Biomedical SciencesNew York Institute of Technology College of Osteopathic MedicineOld WestburyUSA

Personalised recommendations