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BNP in children with congenital cardiac disease: is there now sufficient evidence for its routine use?

Published online by Cambridge University Press:  20 January 2015

Massimiliano Cantinotti
Affiliation:
Fondazione Toscana G. Monasterio, Massa and Pisa, Italy
Henry L. Walters III*
Affiliation:
Department of Cardiovascular Surgery, Children’s Hospital of Michigan, Wayne State University School of Medicine, Detroit, Michigan, United States of America
Maura Crocetti
Affiliation:
Fondazione Toscana G. Monasterio, Massa and Pisa, Italy
Marco Marotta
Affiliation:
Fondazione Toscana G. Monasterio, Massa and Pisa, Italy
Bruno Murzi
Affiliation:
Fondazione Toscana G. Monasterio, Massa and Pisa, Italy
Aldo Clerico
Affiliation:
Fondazione Toscana G. Monasterio, Massa and Pisa, Italy Scuola Superiore Sant’Anna, Pisa, Italy
*
Correspondence to: Dr H. L. Walters III, MD, Chief, Department of Cardiovascular Surgery, Children’s Hospital of Michigan, Wayne State University School of Medicine, 3901 Beaubien Boulevard, Detroit, MI 48201, United States of America. Tel: 313 745 5538; Fax: 313 993 0531; E-mail: [email protected]

Abstract

Interest in brain natriuretic peptide (BNP) and N-terminal pro-brain natriuretic peptide (NT-proBNP) in the management of children with CHD has increased. There are, however, no current guidelines for their routine use. The aim of this review article is to provide an update on the data regarding the use of BNP/NT-proBNP in the evaluation and surgical treatment of children with CHD. BNP/NT-proBNP levels in children with CHD vary substantially according to age, laboratory assay methods, and the specific haemodynamics associated with the individual congenital heart lesion. The accuracy of BNP/NT-proBNP as supplemental markers in the integrated screening, diagnosis, management, and follow-up of CHD has been established. In particular, the use of BNP/NT-proBNP as a prognostic indicator in paediatric cardiac surgery has been widely demonstrated, as well as its role in the subsequent follow-up of surgical patients. Most of the data, however, are derived from single-centre retrospective studies using multivariable analysis; prospective, randomised clinical trials designed to evaluate the clinical utility and cost-effectiveness of routine BNP/NT-proBNP use in CHD are lacking. The results of well-designed, prospective clinical trials should assist in formulating guidelines and expert consensus recommendations for its use in patients with CHD. Finally, the use of new point-of-care testing methods that use less invasive sampling techniques – capillary blood specimens – may contribute to a more widespread use of the BNP assay, especially in neonates and infants, as well as contribute to the development of screening programmes for CHD using this biomarker.

Type
Review Articles
Copyright
© Cambridge University Press 2015 

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References

1. Thygesen, K, Mair, J, Mueller, C, et al. Study Group on Biomarkers in Cardiology of the ESC Working Group on Acute Cardiac Care. Recommendations for the use of natriuretic peptides in acute cardiac care: a position statement from the study group on biomarkers in Cardiology of the ESC working group on Acute Cardiac Care. Eur Heart J 2012; 33: 20012006.Google Scholar
2. Yancy, CW, Jessup, M, Bozkurt, B, et al. ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association task force on practice guidelines. J Am Coll Cardiol, 2013; 62: e147e239.Google Scholar
3. National Institute of Clinical Excellence (NICE). Clinical Guideline 5. Chronic heart failure. Management of chronic heart failure in adults in primary and secondary care. London, July 2003, 1–44.Google Scholar
4. Swedberg, K, Cleland, J, Dargie, H, et al. Task Force for the Diagnosis and Treatment of Chronic Heart Failure of the European Society of Cardiology. Guidelines for the diagnosis and treatment of chronic heart failure: executive summary (update 2005): The task force for the diagnosis and treatment of chronic heart failure of the European Society of Cardiology. Eur Heart J 2005; 26: 11151140.Google Scholar
5. Nieminen, MS, Böhm, M, Cowie, MR, et al. ESC Committe for Practice Guideline (CPG). Executive summary of the guidelines on the diagnosis and treatment of acute heart failure: the task force on Acute Heart failure of the European Society of Cardiology. Eur Heart J 2005; 26: 384416.Google Scholar
6. Hunt, SA, American College of Cardiology; American Heart Association Task Force on Practice Guidelines (Writing Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart Failure). ACC/AHA 2005 guideline update for the diagnosis and management of chronic heart failure in the adult: a report of the American College of Cardiology/American Heart association task force on practice guidelines (writing committee to update the 2001 guidelines for the evaluation and management of heart failure). J Am Coll Cardiol 2005; 46: e1e82.Google Scholar
7. Emdin, E, Clerico, A, Clemenza, F, et al. Recommendations for the clinical use of cardiac natriuretic peptides. J Cardiovasc Med (Ital Heart J) 2005; 6: 430446.Google Scholar
8. Cantinotti, M, Giovannini, S, Murzi, B, Clerico, A. Diagnostic, prognostic and therapeutic relevance of B-type natriuretic peptide assay in children with congenital heart diseases. Clin Chem Lab Med 2011; 49: 567580.Google Scholar
9. Eindhoven, JA, van den Bosch, AE, Jansen, PR, Boersma, E, Roos-Hesselink, JW. The usefulness of brain natriuretic peptide in complex congenital heart disease: a systematic review. J Am Coll Cardiol 2012; 60: 21402149.CrossRefGoogle ScholarPubMed
10. Cantinotti, M, Law, Y, Vittorini, S, et al. The potential and limitations of plasma BNP measurement in the diagnosis, prognosis, and management of children with heart failure due to congenital cardiac disease: an update. Heart Fail Rev 2014; 19: 727--742.Google Scholar
11. Sackett, DL, Haynes, RB. Evidence base of clinical diagnosis. The architecture of diagnostic research. Br Med J 2002; 324: 539541.Google Scholar
12. Price, PC, Christensen, RH. Evidence-Based Laboratory Medicine: Principles, Practice, and Outcome, 2nd edn. AACC Press, Washington, DC, 2007, 1–545.Google Scholar
13. Clerico, A, Recchia, FA, Passino, C, Emdin, M. Cardiac endocrine function is an essential component of the homeostatic regulation network: physiological and clinical implications. Am J Physiol Heart Circ Physiol 2006; 290: H17H29.CrossRefGoogle ScholarPubMed
14. Clerico, A, Giannoni, A, Vittorini, S, Passino, C. Thirty years of the heart as an endocrine organ: physiological role and clinical utility of cardiac natriuretic hormones. Am J Physiol Heart Circ Physiol 2011; 301: H12H20.Google Scholar
15. Liang, F, O'Rear, J, Schellenberger, U, et al. Evidence for functional heterogeneity of circulating B-type natriuretic peptide. J Am Coll Cardiol 2007; 49: 10711078.CrossRefGoogle ScholarPubMed
16. Goetze, JP. Biochemistry of pro-B-type natriuretic peptide-derived peptides: the endocrine heart revisited. Clin Chem 2004; 49: 15031510.Google Scholar
17. Goetze, JP. ProBNP-derived peptides in cardiac disease. Scand J Clin Lab Invest 2004; 64: 497510.Google Scholar
18. Giuliani, I, Rieunier, F, Larue, C, et al. Assay for measurement of intact B-type natriuretic peptide prohormone in blood. Clin Chem 2006; 52: 10541061.Google Scholar
19. Seferian, KR, Tamm, NN, Semenov, AG, et al. The brain natriuretic peptide (BNP) precursor is the major immunoreactive form of BNP in patients with heart failure. Clin Chem 2007; 53: 866873.CrossRefGoogle ScholarPubMed
20. Hammerer-Lercher, A, Halfinger, B, Sarg, B, et al. Analysis of circulating forms of proBNP and NT-proBNP in patients with severe heart failure. Clin Chem 2008; 54: 858865.Google Scholar
21. Goetze, JP, Rehfeld, JF. Peptide hormones and their prohormones as biomarkers. Biomark Med 2009; 3: 335338.CrossRefGoogle ScholarPubMed
22. Dries, DJ, Ky, B, Wu, A, Rame, JE, Putt, M, Cappola, T. Simultaneous assessment of unprocessed ProBNP 1-108 in addition to processed BNP32 improves risk stratification in ambulatory patients with systolic heart ailure. Circ Heart Fail 2010; 3: 220227.Google Scholar
23. Goetze, JP, Kastrup, J, Rehfeld, JF. The paradox of increased natriuretic hormones in congestive heart failure patients: does the endocrine heart also fail in heart failure? Eur Heart J 2003; 24: 14711472.Google Scholar
24. Goetze, JP, Kastrup, J, Pedersen, F, Rehfeld, JF. Quantification of pro-B-type natriuretic peptide and its products in human plasma by use of an analysis independent of precursor processing. Clin Chem 2002; 48: 10351042.Google Scholar
25. Macheret, F, Boerrigter, G, McKie, P, et al. Pro-B-type natriuretic peptide 1-108 circulates in the general community: plasma determinants and detection of left ventricular systolic dysfunction. J Am Coll Cardiol 2011; 57: 13861395.Google Scholar
26. Shimizu, H, Masuta, K, Aono, K, et al. Molecular forms of human brain natriuretic peptide in plasma. Clin Chim Acta 2002; 316: 129135.CrossRefGoogle ScholarPubMed
27. Shimizu, H, Masuta, K, Asada, H, Sugita, K, Sairenji, T. Characterization of molecular forms of probrain natriuretic peptide in human plasma. Clin Chim Acta 2003; 334: 233239.CrossRefGoogle ScholarPubMed
28. Schellenberger, U, O'Rear, J, Guzzetta, A, Jue, RA, Protter, AA, Pollitt, NS. The precursor to B-type natriuretic peptide is an O-linked glycoprotein. Arch Biochem Biophys 2006; 451: 160166.Google Scholar
29. Seferian, KR, Tamm, NN, Semenov, AG, et al. Immunodetection of glycosylated NT-proBNP circulating in human blood. Clin Chem 2008; 54: 866873.Google Scholar
30. Crimmins, DL, Kao, JL. A glycosylated form of the human cardiac hormone pro B-type natriuretic peptide is an intrinsically unstructured monomeric protein. Arch Biochem Biophys 2008; 475: 3641.Google Scholar
31. Semenov, AG, Postnikov, AB, Tamm, NN, et al. Processing of pro-brain natriuretic peptide is suppressed by O-glycosylation in the region close to the cleavage site. Clin Chem 2009; 55: 489498.Google Scholar
32. Miller, WL, Phelps, MA, Wood, CM, et al. Comparison of mass spectrometry and clinical assay measurements of circulating fragments of B-Type natriuretic peptide in patients with chronic heart failure. Circ Heart Fail 2011; 4: 355360.Google Scholar
33. Semenov, AG, Tamm, NN, Seferian, KR, et al. Processing of pro-B-type natriuretic peptide: furin and corin as candidate convertases. Clin Chem 2010; 56: 11661176.CrossRefGoogle ScholarPubMed
34. Jiang, J, Wu, S, Wang, W, et al. Ectodomain shedding and autocleavage of the cardiac membrane protease corin. J Biol Chem 2011; 286: 1006610072.Google Scholar
35. Knappe, S, Wu, F, Masikat, MR, Wu, Q. Functional analysis of the transmembrane domain and activation cleavage of human corin: design and characterization of a soluble corin. J Biol Chem 2003; 278: 5236352370.Google Scholar
36. Dong, N, Chen, S, Yang, J, et al. Plasma soluble corin in patients with heart failure. Circ Heart Fail 2010; 3: 207211.Google Scholar
37. Semenov, AG, Seferian, KR, Tamm, NN, et al. Human pro-B-type natriuretic peptide is processed in the circulation in a rat model. Clin Chem 2011; 57: 883890.CrossRefGoogle ScholarPubMed
38. Rawlins, ML, Owen, WE, Roberts, WL. Performance characteristics of four automated natriuretic peptide assays. Am J Clin Pathol 2005; 123: 439445.CrossRefGoogle ScholarPubMed
39. Prontera, C, Zaninotto, M, Giovannini, S, et al. Proficiency testing project for brain natriuretic peptide (BNP) and the N-terminal part of the propeptide of BNP (NT-proBNP) immunoassays: the CardioOrmoCheck study. Clin Chem Lab Med 2009; 47: 762768.Google Scholar
40. Clerico, A, Zaninotto, M, Prontera, C, et al. State of the art of BNP and NT-proBNP immunoassays: the CardioOrmoCheck study. Clin Chim Acta 2012; 414: 112119.Google Scholar
41. Franzini, M, Masotti, S, Prontera, C, et al. Systematic differences between BNP immunoassays: comparison of methods using standard protocols and quality control materials. Clin Chim Acta 2013; 424: 287291.CrossRefGoogle ScholarPubMed
42. Luckenbill, KN, Christenson, RH, Jaffe, AS, et al. Cross-reactivity of BNP, NT-proBNP, and proBNP in commercial BNP and NT-proBNP assays: preliminary observations from the IFCC committee for standardization of markers of cardiac damage. Clin Chem 2008; 54: 619621.Google Scholar
43. Clerico, A, Zucchelli, GC, Pilo, A, Passino, C, Emdin, M. Clinical relevance of biological variation: the lesson of brain natriuretic peptide (BNP) and NT-proBNP assay. Clin Chem Lab Med 2006; 44: 366378.Google Scholar
44. Nir, A, Lindinger, A, Rauh, M, et al. NT-Pro-B-type natriuretic peptide in infants and children: reference values based on combined data from four studies. Pediatr Cardiol 2009; 30: 38.Google Scholar
45. Mir, TS, Flato, M, Falkenberg, J, Haddad, M, Budden, R, Weil, J. Plasma concentrations of N-terminal brain natriuretic peptide in healthy children, adolescents, and young adults: effect of age and gender. Pediatr Cardiol 2006; 27: 7377.CrossRefGoogle Scholar
46. Mansoub, S, Chan, MK, Adeli, K. Gap analysis of pediatric reference intervals for risk biomarkers of cardiovascular disease and the metabolic syndrome. Clin Biochem 2006; 39: 569587.Google Scholar
47. Koch, A, Singer, M. Normal values of B type natriuretic peptide in infants, children, and adolescents. Heart 2003; 89: 875878.Google Scholar
48. Mir, TS, Laux, R, Hellwege, HH, et al. Plasma concentrations of aminoterminal pro atrial natriuretic peptide and aminoterminal pro brain natriuretic peptide in healthy neonates: marked and rapid increase after birth. Pediatrics 2003; 112: 896899.Google Scholar
49. Nir, A, Bar-Oz, B, Perles, Z, Brooks, R, Korach, A, Rein, AJ. N-terminal pro-B-type natriuretic peptide: reference plasma levels from birth to adolescence. Elevated levels at birth and in infants and children with heart diseases. Acta Paediatr 2004; 93: 603607.Google Scholar
50. Kunii, Y, Kamada, M, Ohtsuki, S, Araki, T, Kataoka, K, Kageyama, M. Plasma brain natriuretic peptide and the evaluation of volume overload in infants and children with congenital heart disease. Acta Med Okayama 2003; 57: 191197.Google Scholar
51. Rauh, M, Koch, A. Plasma N-terminal pro-B-type natriuretic peptide concentrations in a control population of infants and children. Clin Chem 2003; 49: 15631564.Google Scholar
52. Schwachtgen, L, Herrmann, M, Georg, T, Schwarz, P, Marx, N, Lindinger, A. Reference values of NT-proBNP serum concentrations in the umbilical cord blood and in healthy neonates and children. Z Kardiol 2005; 94: 399404.Google Scholar
53. Albers, S, Mir, TS, Haddad, M, Läer, S. N-Terminal pro-brain natriuretic peptide: normal ranges in the pediatric population including method comparison and inter-laboratory variability. Clin Chem Lab Med 2006; 44: 8085.Google Scholar
54. Cantinotti, M, Storti, S, Parri, MS, Murzi, M, Clerico, A. Reference values for plasma B-type natriuretic peptide in the first days of life. Clin Chem 2009; 55: 14381440.CrossRefGoogle ScholarPubMed
55. Soldin, SJ, Soldin, OP, Boyajian, AJ, Taskier, MS. Pediatric brain natriuretic peptide and N-terminal pro-brain natriuretic peptide reference intervals. Clin Chim Acta 2006; 366: 304308.Google Scholar
56. Maffei, S, Del Ry, S, Prontera, C, Clerico, A. Increase in circulating levels of cardiac natriuretic peptides after hormone replacement therapy in postmenopausal women. Clin Sci 2001; 101: 447453.Google Scholar
57. Chang, AY, Abdullah, SM, Jain, T, et al. Associations among androgens, estrogens, and natriuretic peptides in young women: observations from the Dallas Heart Study. J Am Coll Cardiol 2007; 49: 109116.Google Scholar
58. Saenger, AK, Dalenberg, DA, Bryant, SC, Grebe, SK, Jaffe, AS. Pediatric brain natriuretic peptide concentrations vary with age and sex and appear to be modulated by testosterone. Clin Chem 2009; 55: 18691875.Google Scholar
59. Hammerer-Lercher, A, Puschendorf, B, Sommer, R, et al. Natriuretic peptides correlate between newborn twins but not between twins and their mothers. Clin Chim Acta 2007; 377: 279280.Google Scholar
60. Halse, KG, Lindegaard, ML, Goetze, JP, Damm, P, Mathiesen, ER, Nielsen, LB. Increased plasma pro-B-type natriuretic peptide in infants of women with type 1 diabetes. Clin Chem 2005; 51: 22962302.CrossRefGoogle ScholarPubMed
61. Nybo, M, Nielsen, LB, Nielsen, SJ, et al. Discordant expression of pro-B-type and pro-C-type natriuretic peptide in newborn infants of mothers with type 1 diabetes. Regul Pept 2007; 41: 135139.Google Scholar
62. Kanbe, T, Maeno, Y, Fujino, H, et al. Brain-type natriuretic peptide at birth reflects fetal maturation and antenatal stress. Acta Paediatr 2009; 98: 14211425.Google Scholar
63. De Bold, AJ, Ma, KKY, Zhang, Y, Kuroski de Bold, ML, Bensimon, M, Khoshbaten, A. The physiological and pathophysiological modulation of the endocrine function of the heart. Can J Physiol Pharmacol 2001; 79: 705714.Google Scholar
64. Sakata, Y, Yamamoto, K, Masuyama, T, et al. Ventricular production of natriuretic peptides and ventricular structural remodelling in hypertensive heart failure. J Hypertens 2001; 19: 19051909.Google Scholar
65. Takahashi, N, Saito, Y, Kuwahara, K, et al. Angiotensin II-induced ventricular hypertrophy and extracellular signal-regulated kinase activation are suppressed in mice overexpressing brain natriuretic peptide in circulation. Hypertens Res 2003; 26: 847853.Google Scholar
66. Walther, T, Klostermann, K, Hering-Walther, S, Schultheiss, HP, Tschope, C, Stepan, H. Fibrosis rather than blood pressure determines cardiac BNP expression in mice. Regul Pept 2003; 116: 95100.Google Scholar
67. Toth, M, Vuorinen, KH, Vuolteenaho, O, et al. Hypoxia stimulates release of ANP and BNP from perfused rat ventricular myocardium. Am J Physiol 1994; 266: H1572H1580.Google Scholar
68. Baxter, GF. Natriuretic peptides and myocardial ischaemia. Basic Res Cardiol 2004; 99: 9093.Google Scholar
69. Jernberg, T, James, S, Lindahl, B, et al. Natriuretic peptides in unstable coronary artery disease. Eur Heart J 2004; 25: 14861493.Google Scholar
70. Goetze, JP, Gore, A, Moller, CH, Steinbruchel, DA, Rehfeld, JF, Nielsen, LB. Acute myocardial hypoxia increases BNP gene expression. FASEB J 2004; 18: 19291930.Google Scholar
71. Casals, G, Ros, J, Sionis, A, Davidson, MM, Morales-Ruiz, M, Jiménez, W. Hypoxia induces B-type natriuretic peptide release in cell lines derived from human cardiomyocytes. Am J Physiol Heart Circ Physiol 2009; 297: H550H555.Google Scholar
72. Chun, YS, Hyun, JY, Kwak, YG, et al. Hypoxic activation of the atrial natriuretic peptide gene promoter through direct and indirect actions of hypoxia-inducible factor-1. Biochem J 2003; 370: 149157.Google Scholar
73. Clerico, A. Pathophysiological and clinical relevance of circulating levels of cardiac natriuretic hormones: is their assay merely a marker of cardiac disease? Clin Chem Lab Med 2002; 40: 752760.Google Scholar
74. Clerico, A, Zucchelli, GC, Pilo, A, Emdin, M. Clinical relevance of biological variation of B-type natriuretic peptide. Clin Chem 2005; 51: 925926.Google Scholar
75. Clerico, A, Fontana, M, Ripoli, A, Emdin, M. Clinical relevance of BNP measurement in the follow-up of patients with chronic heart failure. Adv Clin Chem 2009; 48: 163179.Google Scholar
76. Januzzi, JL, Troughton, R. Are serial BNP measurements useful in heart failure management? Serial natriuretic peptide measurements are useful in heart failure management. Circulation 2013; 127: 500508.Google Scholar
77. Cantinotti, M, Storti, S, Parri, MS, Prontera, C, Murzi, B, Clerico, A. Reference intervals for brain natriuretic peptide in healthy newborns and infants measured with an automatedimmunoassay platform. Clin Chem Lab Med 2010; 48: 697700.Google Scholar
78. Holmgren, D, Westerlind, A, Lundberg, PA, Wahlander, H. Increased plasma levels of natriuretic peptide type B and A in children with congenital heart defects with left compared with right ventricular volume overload or pressure overload. Clin Physiol Funct Imaging 2005; 25: 263269.Google Scholar
79. Koch, A, Zink, S, Singer, H, Dittrich, S. B-type natriuretic peptide levels in patients with functionally univentricular hearts after total cavo-pulmonary connection. Eur J Heart Fail 2008; 10: 6062.Google Scholar
80. Holmgren, D, Westerlind, A, Berggren, H, Lundberg, PA, Wahlander, H. Increased natriuretic peptide type B level after the second palliative step in children with univentricular hearts with right ventricular morphology but not left ventricular morphology. Pediatr Cardiol 2008; 29: 786792.Google Scholar
81. Koch, A, Zink, S, Singer, H. B-type natriuretic peptide in paediatric patients with congenital heart disease. Eur Heart J 2006; 27: 861866.Google Scholar
82. Cowley, CG, Bradley, JD, Shaddy, RE. B-type natriuretic peptide levels in congenital heart disease. Pediatr Cardiol 2004; 25: 336340.CrossRefGoogle ScholarPubMed
83. Price, JF, Thomas, AK, Grenier, M, et al. B-type natriuretic peptide predicts adverse cardiovascular events in pediatric outpatients with chronic left ventricular systolic dysfunction. Circulation 2006; 114: 10631069.Google Scholar
84. Kaski, JP, Tomé-Esteban, MT, Mead-Regan, S, et al. B-type natriuretic peptide predicts disease severity in children with hypertrophic cardiomyopathy. Heart 2008; 94: 13071311.Google Scholar
85. Sangeev, S, Pettersen, M, Lua, J, Thomas, R, Shankaran, S, L'Ecuyer, T. Role of plasma B-type natriuretic peptide in screening for hemodynamically significant patent ductus arteriosus in preterm neonates. J Perinatol 2005; 25: 709713.Google Scholar
86. Mir, TS, Marohn, S, Läer, S, Eiselt, M, Grollmus, O, Weil, J. Plasma concentrations of N-terminal pro-brain natriuretic peptide in control children from the neonatal to adolescent period and in children with congestive heart failure. Pediatrics 2002; 110: e76e81.Google Scholar
87. Häusermann, E, Fasnacht, M, Hersberger, M, Gessler, P, Bauersfeld, U. Plasma B-type natriuretic peptide levels in children with heart disease. Acta Paediatr 2011; 100: 12131216.Google Scholar
88. Hongkan, W, Soongswang, J, Veerakul, G, et al. N-terminal pro brain natriuretic peptide and cardiac function in doxorubicin administered pediatric patients. J Med Assoc Thai 2009; 92: 14501457.Google Scholar
89. Kervancioglu, M. Plasma concentrations of NT-pro-BNP and cardiac troponin-I in relation to doxorubicin-induced cardiomyopathy and cardiac function in childhood malignancy. Saudi Med J 2005; 26: 11971202.Google Scholar
90. Komada, Y, Hirayama, M, Hori, H, Ito, M, Sakurai, M. Plasma levels of natriuretic peptides in relation to doxorubicin-induced cardiotoxicity and cardiac function in children with cancer. Med Pediatr Oncol 2001; 37: 49.Google Scholar
91. Phil, M, Khan, DA, Tuyyab, F. Early detection of cardiac dysfunction by BNP in beta-thalassaemia major patients. Acta Cardiol 2012; 67: 331335.Google Scholar
92. Aggarwal, S, Pettersen, MD, Bhambhani, K, Gurczynski, J, Thomas, R, L'Ecuyer, T. B-type natriuretic peptide as a marker for cardiac dysfunction in anthracycline-treated children. Pediatr Blood Cancer 2007; 49: 812816.Google Scholar
93. Saji, T, Takatsuki, S, Fujiwara, M. Abnormal tissue Doppler images are associated with elevated plasma brain natriuretic peptide and increased oxidative stress in acute Kawasaki disease. Circ J 2007; 71: 357362.Google Scholar
94. Pletcher, MJ, Pignone, M. Evaluating the clinical utility of a biomarker: a review of methods for estimating health impact. Circulation 2011; 123: 11161124.Google Scholar
95. Wang, TJ. Assessing the role of circulating, genetic, and imaging biomarkers in cardiovascular risk prediction. Circulation 2011; 123: 551565.Google Scholar
96. Hlatky, MA, Greenland, P, Arnett, DK, et al. Criteria for evaluation of novel markers of cardiovascular risk: a scientific statement from the American Heart Association. Circulation 2009; 119: 24082416.Google Scholar
97. Davlouros, PA, Karatza, AA, Xanthopoulou, I, et al. Diagnostic role of plasma BNP levels in neonates with signs of congenital heart disease. Int J Cardiol 2011; 147: 4246.Google Scholar
98. Ko, HK, Lee, JH, Choi, BM, et al. Utility of the rapid B-type natriuretic peptide assay for detection of cardiovascular problems in newborn infants with respiratory difficulties. Neonatology 2008; 94: 1621.Google Scholar
99. Koulouri, S, Acherman, RJ, Wong, PC, Chan, LS, Lewis, AB. Utility of B-type natriuretic peptide in differentiating congestive heart failure from lung disease in pediatric patients with respiratory distress. Pediatr Cardiol 2004; 25: 341346.Google Scholar
100. Maher, KO, Reed, H, Cuadrado, A, et al. B-type natriuretic peptide in the emergency diagnosis of critical heart disease in children. Pediatrics 2008; 121: e1484e1488.Google Scholar
101. Cohen, S, Springer, C, Avital, A, et al. Amino-terminal pro-brain-type natriuretic peptide: heart or lung disease in pediatric respiratory distress? Pediatrics 2005; 115: 13471350.Google Scholar
102. Law, YM, Hoyer, AW, Reller, MD, Silberbach, M. Accuracy of plasma B-type natriuretic peptide to diagnose significant cardiovascular disease in children: the better not pout children! Study. J Am Coll Cardiol 2009; 54: 14671475.Google Scholar
103. Zhao, QM, Ma, XJ, Ge, XL. Pulse oximetry with clinical assessment to screen for congenital heart disease in neonates in China: a prospective study. Lancet 2014; 384: 747754.Google Scholar
104. Thangaratinam, S, Brown, K, Zamora, J, Khan, KS, Ewer, AK. Pulse oximetry screening for critical congenital heart defects in asymptomatic newborn babies: a systematic review and meta-analysis. Lancet 2012; 379: 24592464.Google Scholar
105. Cantinotti, M, Vittorini, S, Storti, S, et al. Diagnostic accuracy and clinical relevance of brain natriuretic peptide assay in pediatric patients with congenital heart diseases. J Cardiovasc Med (Hagerstown) 2009; 10: 706713.Google Scholar
106. Czernik, C, Lemmer, J, Metze, B, Koehne, PS, Mueller, C, Obladen, M. B-type natriuretic peptide to predict ductus intervention in infants <28 weeks. Pediatr Res 2008; 64: 286290.Google Scholar
107. Farombi-Oghuvbu, I, Matthews, T, Mayne, PD, Guerin, H, Corcoran, JD. N-terminal pro-B-type natriuretic peptide: a measure of significant patent ductus arteriosus. Arch Dis Child Fetal Neonatal Ed 2008; 93: F257F260.Google Scholar
108. Eerola, A, Jokinen, E, Boldt, T, Pihkala, J. The influence of percutaneous closure of patent ductus arteriosus on left ventricular size and function: a prospective study using two- and three dimensional echocardiography and measurements of serum natriuretic peptides. J Am Coll Cardiol 2006; 47: 10601066.Google Scholar
109. Flynn, PA, da Graca, RL, Auld, PA, Nesin, M, Kleinman, CS. The use of a bedside assay for plasma B-type natriuretic peptide as a biomarker in the management of patent ductus arteriosus in premature neonates. J Pediatr 2005; 147: 3842.Google Scholar
110. Tosse, V, Pillekamp, F, Verde, P, et al. Urinary NT-proBNP, NGAL, and H-FABP may predict hemodynamic relevance of patent ductus arteriosus in very low birth weight infants. Neonatology 2012; 101: 260266.Google Scholar
111. Kalra, VK, DeBari, VA, Zauk, A, Kataria, P, Myridakis, D, Kiblawi, F. Point-of-care testing for B-type natriuretic peptide in premature neonates with patent ductus arteriosus. Ann Clin Lab Sci 2011; 41: 131137.Google Scholar
112. Cantinotti, M, Assanta, N, Murzi, B, Lopez, L. Controversies in the definition and management of insignificant left-to-right shunts. Heart 2014; 100: 200205.Google Scholar
113. Berry, JG, Askovich, B, Shaddy, RE, Hawkins, JA, Cowley, CG. Prognostic value of B-type natriuretic peptide in surgical palliation of children with single-ventricle congenital heart disease. Pediatr Cardiol 2008; 29: 7075.Google Scholar
114. Hsu, JH, Keller, RL, Chikovani, O, et al. B-type natriuretic peptide levels predict outcome after neonatal cardiac surgery. J Thorac Cardiovasc Surg 2007; 134: 939944.Google Scholar
115. Walsh, R, Boyer, C, LaCorte, J, et al. N-terminal B-type natriuretic peptide levels in pediatric patients with congestive heart failure undergoing cardiac surgery. J Thorac Cardiovasc Surg 2008; 135: 98105.Google Scholar
116. Shih, CY, Sapru, A, Oishi, P, et al. Alterations in plasma B-type natriuretic peptide levels after repair of congenital heart defects: a potential perioperative marker. J Thorac Cardiovasc Surg 2006; 131: 632638.Google Scholar
117. Cannesson, M, Bionda, C, Gostoli, B, et al. Time course and prognostic value of plasma B-type natriuretic peptide concentration in neonates undergoing the arterial switch operation. Anesth Analg 2007; 104: 10591065; tables of contents.Google Scholar
118. Mir, TS, Haun, C, Lilje, C, Läer, S, Weil, J. Utility of N-terminal brain natriuretic peptide plasma concentrations in comparison to lactate and troponin in children with congenital heart disease following open-heart surgery. Pediatr Cardiol 2006; 27: 209216.Google Scholar
119. Koch, A, Kitzsteiner, T, Zink, S, Cesnjevar, R, Singer, H. Impact of cardiac surgery on plasma levels of B-type natriuretic peptide in children with congenital heart disease. Int J Cardiol 2007; 114: 339344.Google Scholar
120. Gessler, P, Knirsch, W, Schmitt, B, Rousson, V, von Eckardstein, A. Prognostic value of plasma N-terminal pro-brain natriuretic peptide in children with congenital heart defects and open-heart surgery. J Pediatr 2006; 148: 372376.Google Scholar
121. Niedner, MF, Foley, JL, Riffenburgh, RH, Bichell, DP, Peterson, BM, Rodarte, A. B-type natriuretic peptide: peri-operative patterns in congenital heart disease. Congenit Heart Dis 2010; 5: 243255.Google Scholar
122. Amirnovin, R, Keller, RL, Herrera, C, et al. B-type natriuretic peptide levels predict outcomes in infants undergoing cardiac surgery in a lesion-dependent fashion. J Thorac Cardiovasc Surg 2013; 145: 12791287.Google Scholar
123. Cantinotti, M, Clerico, A, Iervasi, G. Age and disease related variations in BNP response after pediatric cardiac surgery. J Thorac Cardiovasc Surg 2013; 145: 14151416.Google Scholar
124. Cantinotti, M, Lorenzoni, V, Storti, S, et al. Thyroid and BNP Response in Children Undergoing Cardiac Surgery for Congenital Heart Disease: age related variations and prognostic value. Circ J 2012; 77: 188197.CrossRefGoogle ScholarPubMed
125. Lindblade, CL, Chun, DS, Darragh, RK, Caldwell, RL, Murphy, DJ, Schamberger, MS. Value of plasma B-type natriuretic peptide as a marker for rejection in pediatric heart transplant recipients. Am J Cardiol, 2005; 95: 909911.Google Scholar
126. Hammerer-Lercher, A, Mair, J, Antretter, H, et al. B-type natriuretic peptide as a marker of allograft rejection after heart transplantation. J Heart Lung Transplant 2005; 24: 1444.e51448.e8.Google Scholar
127. Lan, YT, Chang, RK, Alejos, JC, Burch, C, Wetzel, GT. B-type natriuretic peptide in children after cardiac transplantation. J Heart Lung Transplant 2004; 23: 558563.Google Scholar
128. Ationu, A, Burch, M, Singer, D, Littleton, P, Carter, N. Cardiac transplantation affects ventricular expression of brain natriuretic peptide. Cardiovasc Res 1993; 27: 188189.Google Scholar
129. Claudius, I, Lan, YT, Chang, RK, Wetzel, GT, Alejos, J. Usefulness of B-type natriuretic peptide as a noninvasive screening tool for cardiac allograft pathology in pediatric heart transplant recipients. Am J Cardiol 2003; 92: 13681370.Google Scholar
130. Ationu, A, Sorensen, K, Whitehead, B, Singer, D, Burch, M, Carter, ND. Ventricular expression of brain natriuretic peptide gene following orthotopic cardiac transplantation in children – a three year follow up. Cardiovasc Res 1993; 27: 21352139.Google Scholar
131. Heise, G, Lemmer, J, Weng, Y, et al. Biomarker responses during mid-term mechanical cardiac support in children. J Heart Lung Transplant 2008; 27: 150157.Google Scholar
132. Szymanski, P, Klisiewicz, A, Lubiszewska, B, et al. Functional anatomy of tricuspid regurgitation in patients with systemic right ventricles. J Am Soc Echocardiogr 2010; 23: 504510.Google Scholar
133. Shah, A, Feraco, AM, Harmon, C, Tacy, T, Fineman, JR, Bernstein, HS. Usefulness of various plasma biomarkers for diagnosis of heart failure in children with single ventricle physiology. Am J Cardiol 2009; 104: 12801284.Google Scholar
134. Lowenthal, A, Camacho, BV, Lowenthal, S, et al. Usefulness of B-type natriuretic peptide and N-terminal pro-B-type natriuretic peptide as biomarkers for heart failure in young children with single ventricle congenital heart disease. Am J Cardiol 2012; 109: 866872.Google Scholar
135. Atz, AM, Zak, V, Breitbart, RE, et al. Factors associated with serum brain natriuretic peptide levels after the Fontan procedure. Congenit Heart Dis 2011; 6: 313321.Google Scholar
136. Lechner, E, Schreier-Lechner, EM, Hofer, A, et al. Amino-terminal brain-type natriuretic peptide levels correlate with heart failure in patients with bidirectional Glenn anastomosis and with morbidity after the Fontan operation. J Thorac Cardiovasc Surg 2009; 138: 560564.Google Scholar
137. Hsu, JH, Oishi, PE, Keller, RL, et al. Perioperative B-type natriuretic peptide levels predict outcome after bidirectional cavo-pulmonary anastomosis and total cavo-pulmonary connection. J Thorac Cardiovasc Surg 2008; 135: 746753.Google Scholar
138. Law, YM, Ettedgui, J, Beerman, L, Maisel, A, Tofovic, S. Comparison of plasma B-type natriuretic peptide levels in single ventricle patients with systemic ventricle heart failure versus isolated cavo-pulmonary failure. Am J Cardiol 2006; 98: 520524.Google Scholar
139. Anderson, PA, Sleeper, LA, Mahony, L, et al. Contemporary outcomes after the Fontan procedure: a pediatric heart network multicenter study. J Am Coll Cardiol 2008; 52: 114116.Google Scholar
140. Hjortdal, VE, Stenbog, EV, Ravn, HB, et al. Neurohormonal activation late after cavo-pulmonary connection. Heart 2000; 83: 439443.Google Scholar
141. Ohuchi, H, Takasugi, H, Ohashi, H, et al. Abnormalities of neurohormonal and cardiac autonomic nervous activities relate poorly to functional status in Fontan patients. Circulation 2004; 110: 26012608.Google Scholar
142. Holmgren, D, Stromvall-Larsson, E, Lundberg, PA, Eriksson, BO, Wahlander, H. Brain natriuretic peptide assessed at long-term follow-up before and after maximal exercise in surgically palliated patients with functionally univentricular hearts. Cardiol Young 2007; 17: 505511.Google Scholar
143. Man, BL, Cheung, YF. Plasma brain natriuretic peptide and systemic ventricular function in asymptomatic patients late after the Fontan procedure. Heart Vessels 2007; 22: 398403.Google Scholar
144. Robbers-Visser, D, Kapusta, L, van Osch-Gevers, L, et al. Clinical outcome 5 to 18 years after the Fontan operation performed on children younger than 5 years. J Thorac Cardiovasc Surg 2009; 138: 8995.Google Scholar
145. Inai, K, Nakanishi, T, Nakazawa, M. Clinical correlation and prognostic predictive value of neurohumoral factors in patients late after the Fontan operation. Am Heart J 2005; 150: 588594.Google Scholar
146. Lechner, E, Gitter, R, Mair, R, et al. Amino-terminal brain natriuretic peptide levels in children and adolescents after Fontan operation correlate with congestive heart failure. Pediatr Cardiol 2008; 29: 901905.Google Scholar
147. Wahlander, H, Westerlind, A, Lindstedt, G, Lundberg, PA, Holmgren, D. Increased levels of brain and atrial natriuretic peptides after the first palliative operation, but not after a bidirectional Glenn anastomosis, in children with functionally univentricular hearts. Cardiol Young 2003; 13: 268274.Google Scholar
148. Motoki, N, Ohuchi, H, Miyazaki, A, Yamada, O. Clinical profiles of adult patients with single ventricular physiology. Circ J 2009; 73: 17111716.Google Scholar
149. Goldberg, DJ, French, B, McBride, MG, et al. Impact of oral sildenafil on exercise performance in children and young adults after the Fontan operation: a randomized, double-blind, placebo-controlled, crossover trial. Circulation 2011; 123: 11851193.Google Scholar
150. Eindhoven, JA, van den Bosch, AE, Ruys, TP, et al. N-terminal Pro-B-type natriuretic peptide and its relationship with cardiac function in adults with congenital heart disease. J Am Coll Cardiol 2013; 24: 12031212.Google Scholar
151. Ravishankar, C, Zak, V, Williams, IA, et al. Association of impaired linear growth and worse neurodevelopmental outcome in infants with single ventricle physiology: a report from the pediatric heart network infant single ventricle trial. J Pediatr 2013; 162: 250256.e2.Google Scholar
152. Saab, FG, Aboulhosn, JA. Hemodynamic characteristics of cyanotic adults with single-ventricle physiology without Fontan completion. Congenit Heart Dis 2013; 8: 124130.Google Scholar
153. Heck, PB, Müller, J, Weber, R, Hager, A. Value of N-terminal pro brain natriuretic peptide levels in different types of Fontan circulation. Eur J Heart Fail 2013; 15: 644649.Google Scholar
154. Chow, PC, Cheung, EW, Chong, CY, et al. Brain natriuretic peptide as a biomarker of systemic right ventricular function in patients with transposition of great arteries after atrial switch operation. Int J Cardiol 2008; 127: 192197.Google Scholar
155. Schaefer, A, Tallone, EM, Westhoff-Bleck, M, Klein, G, Drexler, H, Rontgen, P. Relation of diastolic and systolic function, exercise capacity and brain natriuretic peptide in adults after mustard procedure for transposition of the great arteries. Cardiology 2010; 117: 112117.Google Scholar
156. Larsson, DA, Meurling, CJ, Holmqvist, F, Waktare, JE, Thilen, UJ. The diagnostic and prognostic value of brain natriuretic peptides in adults with a systemic morphologically right ventricle or Fontan-type circulation. Int J Cardiol 2007; 114: 345351.Google Scholar
157. Koch, AM, Zink, S, Singer, H. B-type natriuretic peptide in patients with systemic right ventricle. Cardiology 2008; 110: 17.Google Scholar
158. Garg, R, Raman, SV, Hoffman, TM, Hayes, J, Daniels, CJ. Serum markers of systemic right ventricular function and exercise performance. Pediatr Cardiol 2008; 29: 641648.Google Scholar
159. Plymen, CM, Hughes, ML, Picaut, N, et al. The relationship of systemic right ventricular function to ECG parameters and Nt-proBNP levels in adults with transposition of the great arteries late after Senning or Mustard surgery. Heart 2010; 96: 15691573.Google Scholar
160. Neffke, JG, Tulevski, II, van der Wall, EE, et al. ECG determinants in adult patients with chronic right ventricular pressure overload caused by congenital heart disease: relation with plasma neurohormones and MRI parameters. Heart 2002; 88: 266270.Google Scholar
161. Winter, MM, Bouma, BJ, van Dijk, AP, et al. Relation of physical activity, cardiac function, exercise capacity, and quality of life in patients with a systemic right ventricle. Am J Cardiol 2008; 102: 12581262.Google Scholar
162. Norozi, K, Buchhorn, R, Alpers, V, et al. Relation of systemic ventricular function quantified by myocardial performance index (Tei) to cardiopulmonary exercise capacity in adults after Mustard procedure for transposition of the great arteries. Am J Cardiol 2005; 96: 17211725.Google Scholar
163. Kozelj, M, Prokselj, K, Berden, P, et al. The syndrome of cardiac failure in adults with congenitally corrected transposition. Cardiol Young 2008; 18: 599607.Google Scholar
164. Dore, A, Houde, C, Chan, KL, et al. Angiotensin receptor blockade and exercise capacity in adults with systemic right ventricles: a multicenter, randomized, placebo-controlled clinical trial. Circulation 2005; 112: 24112416.Google Scholar
165. Vogt, M, Kuhn, A, Wiese, J, Eicken, A, Hess, J, Vogel, M. Reduced contractile reserve of the systemic right ventricle under dobutamine stress is associated with increased brain natriuretic peptide levels in patients with complete transposition after atrial repair. Eur J Echocardiogr 2009; 10: 691694.Google Scholar
166. Apitz, C, Sieverding, L, Latus, H, Uebing, A, Schoof, S, Hofbeck, M. Right ventricular dysfunction and B-type natriuretic peptide in asymptomatic patients after repair for tetralogy of Fallot. Pediatr Cardiol 2009; 30: 898904.Google Scholar
167. Oosterhof, T, Tulevski, II, Vliegen, HW, Spijkerboer, AM, Mulder, BJ. Effects of volume and/or pressure overload secondary to congenital heart disease (tetralogy of Fallot or pulmonary stenosis) on right ventricular function using cardiovascular magnetic resonance and B-type natriuretic peptide levels. Am J Cardiol 2006; 97: 10511055.Google Scholar
168. Tulevski, II, Groenink, M, Van Der Wall, FF, Van Velduisen, DJ, Boomsma, F, Stoker, J. Increased brain and atrial natriuretic peptides in patients with chronic right ventricular overload: correlation between plasma neuro-hormones and right ventricular dysfunction. Heart 2001; 86: 2730.Google Scholar
169. Dodge-Khatami, A, Büchel, EV, Knirsch, W, et al. Brain natriuretic peptide and magnetic resonance imaging in tetralogy with right ventricular dilatation. Ann Thorac Surg 2006; 82: 983988.Google Scholar
170. Norozi, K, Buchhorn, R, Bartmus, D, et al. Elevated brain natriuretic peptide and reduced exercise capacity in adult patients operated on for tetralogy of Fallot is due to biventricular dysfunction as determined by the myocardial performance index. Am J Cardiol 2006; 97: 13771382.Google Scholar
171. Ishii, H, Harada, K, Toyono, M, Tamura, M, Takada, G. Usefulness of exercise-induces changes in plasma levels of brain natriuretic peptide in predicting right ventricular contractile reserve after repair of tetralogy of Fallot. Am J Cardiol 2005; 95: 13381343.Google Scholar
172. Cetin, I, Tokel, K, Varan, B, Orun, U, Aslamaci, S. Evaluation of right ventricular function by using tissue Doppler imaging in patients after repair of tetralogy of Fallot. Echocardiography 2009; 26: 950957.Google Scholar
173. Knirsch, W, Dodge-Khatami, A, Kadner, A, et al. Assessment of myocardial function in pediatric patients with operated tetralogy of Fallot: preliminary results with 2D strain echocardiography. Pediatr Cardiol 2008; 29: 718725.Google Scholar
174. Koch, AM, Zink, S, Glockler, M, Seeliger, T, Dittrich, S. Plasma levels of B-type natriuretic peptide in patients with tetralogy of Fallot after surgical repair. Int J Cardiol 2010; 143: 130134.Google Scholar
175. Festa, P, Ait-Ali, L, Prontera, C, et al. Amino-terminal fragment of pro-brain natriuretic hormone identifies functional impairment and right ventricular overload in operated tetralogy of Fallot patients. Pediatr Cardiol 2007; 28: 339345.Google Scholar
176. Brili, S, Alexopoulos, N, Latsios, G, et al. Tissue Doppler imaging and brain natriuretic peptide levels in adults with repaired tetralogy of Fallot. J Am Soc Echocardiogr 2005; 18: 11491154.Google Scholar
177. Tatani, SB, Carvalho, AC, Andriolo, A, Rabelo, R, Campos, O, Moises, VA. Echocardiographic parameters and brain natriuretic peptide in patients after surgical repair of tetralogy of Fallot. Echocardiography 2010; 27: 442447.Google Scholar
178. Wand, O, Perles, Z, Rein, AJ, Algur, N, Nir, A. Clinical. echocardiographic and humoral status of patients following repair of tetralogy of Fallot: comparison of the second to the first decade. Isr Med Assoc J 2007; 9: 843846.Google Scholar
179. Van den Berg, J, Strengers, JL, Wielopolski, PA, et al. Assessment of biventricular functional reserve and NT-proBNP levels in patients with right ventricle volume overload after repair of tetralogy of Fallot at young age. Int J Cardiol 2009; 133: 364370.Google Scholar
180. Khositseth, A, Manop, J, Khowsathit, P, et al. N-terminal pro-brain natriuretic peptide as a marker in follow-up patients with tetralogy of Fallot after total correction. Pediatr Cardiol 2007; 28: 333338.Google Scholar
181. Norozi, K, Bahlmann, J, Raab, B, et al. A prospective, randomized, double-blind, placebo controlled trial of beta-blockade in patients who have undergone surgical correction of tetralogy of Fallot. Cardiol Young 2007; 17: 372379.Google Scholar
182. Roche, SL, Grosse-Wortmann, L, Redington, AN, et al. Exercise induces biventricular mechanical dyssynchrony in children with repaired tetralogy of Fallot. Heart 2010; 96: 20102015.Google Scholar
183. Xu, Z, Zhang, M, Zhu, L, Gong, X, Li, J. Elevated plasma B-type natriuretic peptide and C-reactive protein levels in children with restrictive right ventricular physiology following tetralogy of Fallot repair. Congenit Heart Dis 2014; 9: 521528.Google Scholar
184. Hirono, K, Sekine, M, Shiba, N, et al. N-terminal pro-brain natriuretic peptide as a predictor of reoperation in children with surgically corrected tetralogy of Fallot. Circ J 2014; 78: 693700.Google Scholar
185. Villafañe, J, Feinstein, JA, Jenkins, KJ, et al. Hot topics in tetralogy of Fallot. J Am Coll Cardiol 2013; 62: 21552166.Google Scholar
186. Emdin, M, Vittorini, S, Passino, C, Clerico, A. Old and new biomarkers of heart failure. Eur J Heart Fail 2009; 11: 331335.Google Scholar
187. Januzzi, JL Jr. Natriuretic peptides as biomarkers in heart failure. J Investig Med 2013; 61: 950955.Google Scholar
188. Baer, GR, Nelson, RM. Ethical challenges in neonatal research: summary report of the ethics group of the newborn drug development initiative. Clin Ther 2006; 28: 13991407.Google Scholar
189. Stephenson, T, Budge, H. The future of neonatal therapeutic trials. Arch Dis Child Fetal Neonatal Ed 2006; 91: F305F307.Google Scholar
190. Ligi, I, Boubred, F, Grandvuillemin, I, Simeoni, U. Clinical research in newborn infants: difficulties and specificity. Eur J Clin Pharmacol 2012; 67 (Suppl 1): 2932.Google Scholar