**1. Introduction**

198 Front Lines of Thoracic Surgery

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In 1988 Sudoh and colleagues described a novel natriuretic peptide in porcine brain -- brain natriuretic peptide(Sudoh et al. 1988). In fact, the peptide is most abundant in the heart and thus it is now commonly termed B-type natriuretic peptide (BNP). Myocyte pressure and/or stretch results in the release of BNP, and BNP levels are easily quantified by several commercially available assays. Data from numerous studies have now firmly established a role for BNP as a biomarker for diagnosis, prognostication, and management of adults with cardiac disease, including those undergoing cardiac surgery(Silver et al. 2004; Mitchell and Webb 2011; Rodseth, Padayachee, and Biccard 2008; Fellahi et al. 2011). Unfortunately, far fewer data are available on the role of BNP in the management of neonates, infants, and children who require cardiac surgery. This chapter will provide a brief review of these data in order to understand the potential utility of BNP determinations in this population.

#### **2. Natriuretic hormone system**

Beginning with the observation by de Bold and colleagues that rats infused with atrial tissue extracts developed natriuresis and diuresis, much has been learned over the past three decades about the role of the natriuretic hormone system in the homeostatic control of fluid balance and vascular tone(de Bold et al. 1981). The natriuretic hormone system comprises several related peptides that activate specific receptors, particularly in the kidneys, myocardium, and vasculature, which use cyclic guanosine 3',5'-monophosphate (cGMP) as a second messenger(Levin, Gardner, and Samson 1998). These peptides include atrial natriuretic peptide (ANP), BNP, C-type natriuretic peptide (CNP), dendroaspis natriuretic peptide (DNP), kaliuretic peptide, and urodilantin. The primary stimulus for their release is an increase in intravascular or cardiac volume, that causes increased atrial stretch, ventricular wall stress, vascular shear stress, intravascular volume, and/or intravascular sodium concentration(Levin, Gardner, and Samson 1998). The precise roles of individual natriuretic peptides depend upon their distribution and abundance within the cardiovascular system, as well as the specific stimulus for their release(Levin, Gardner, and Samson 1998).

B-Type Natriuretic Peptide (BNP) in Neonates,

de Bold 2005; Sudoh et al. 1988; Yandle 1994).

proBNP levels than BNP levels.

**4. BNP in pediatric heart disease** 

levels fell in all groups with therapy.

1993).

Infants, and Children Undergoing Cardiac Surgery 201

The mechanisms that mediate BNP release and metabolism in health and disease are incompletely understood. In addition, the effect of development on these mechanisms is unknown, but clearly may have great relevance in a pediatric population. Active BNP is stored in the atria in specific storage organelles(McGrath, de Bold, and de Bold 2005). Basal BNP levels result from continuous secretion from the atria. With acute myocardial distention, BNP release increases from this storage pool, in a manner independent of BNP synthesis. However, under acute, sub-acute and chronic conditions of increased cardiac volume or pressure loading, increases in circulating BNP are maintained due to ventricular re-expression of the fetal gene program (Zhang, Carreras, and de Bold 2003; Hama et al. 1995). In addition to volume and pressure loading, acute myocardial ischemia, α agonist stimulation, endothelin-1, and inflammatory mediators, such as tumor necrosis factor-α and interleukin-1β, result in rapid ventricular expression of BNP(Hama et al. 1995). The primary actions of BNP are vascular smooth muscle relaxation and anti-mitogenesis, mediated by cGMP, diuresis, caused by a shift of intravascular volume into the interstitium, and natriuresis, caused by antagonism of renin and aldosterone release(McGrath, de Bold, and

Of all the natriuretic peptides, BNP has emerged as the most useful biomarker for cardiac disease. Its major advantage over the other natriuretic peptides is the fact that it is produced predominantly in the ventricles, as opposed to the atrium (ANP) or the vascular endothelium (CNP)(Silver et al. 2004; Costello, Goodman, and Green 2006). Both active BNP and the inactive byproduct of its production, NT-proBNP, are used as biomarkers. BNP levels may be better suited to follow dynamic alterations in myocardial performance given the shorter circulating half-life of BNP compared to NT-proBNP (20 minutes vs. 60-120 minutes)(Costello, Goodman, and Green 2006). In addition, the kidneys excrete NT-proBNP, and thus renal function, independent of myocardial function, has a greater influence on NT-

Limited data suggest that BNP levels are high at birth but fall during the first week of life, reaching levels below adult values by 2 weeks of age. Interestingly, although levels in boys tend to decrease with age, girls have an elevation during the second decade of life that is associated with puberty (Koch and Singer 2003; Yoshibayashi et al. 1995; Ationu and Carter

In comparison to the adult experience, there are far fewer data regarding BNP in pediatric cardiac disease(Das 2010). Knirsch and colleagues measured BNP levels before and during treatment in 522 pediatric patients (age of 6.4±5.2 years, range of 14 days to 18 years) with congenital heart disease, cardiomyopathies, or pulmonary arterial hypertension(Knirsch et al. 2011). They found that BNP levels were elevated in each type of heart disease, and that

As opposed to adults with congestive heart failure, BNP levels in infants and children with congenital heart disease are quite varied, and are dependent in part upon the age of the patient and the specific physiology associated with the cardiac defect. For example, Law and colleagues performed a study that included 42 neonates and 58 older children between the age of 7 days and 19 years presenting in an acute care setting with symptoms potentially attributable to heart disease. BNP levels were higher in both age groups in those patients with heart disease compared to those without heart disease, but the cut-off values differed. A BNP level of 170 pg/ml was 94% sensitive and 73% specific for heart disease in neonates,
