Massimiliano Cantinotti

Nomograms for blood flow and tissue Doppler velocities to evaluate diastolic function in children: a critical review.

Interest in diastolic function in children has increased recently. However, the strengths and limitations of published pediatric nomograms for echocardiographic diastolic parameters have not been critically evaluated, especially in the neonatal population. A literature search was performed within the National Library of Medicine using the keywords normal/reference values, power Doppler/tissue Doppler velocities, and children/neonates. The search was further refined by adding the keywords diastolic function, myocardial, mitral/tricuspid inflow, pulmonary vein, and Tei index. Thirty-three published studies evaluating diastolic function in normal children were included in this review. In many studies, sample sizes were limited, particularly in terms of neonates. There was heterogeneity in the methodologies to perform and normalize measurements and to express normalized data (Z scores, percentiles, and mean values). Although most studies adjusted measurements for age, classification by specific age subgroups varied, and few addressed the relationships of measurements to body size and heart rate (especially with higher neonatal heart rates). Although reference values were reproducible in older children, they varied significantly in neonates and infants. Pediatric diastolic nomograms are limited by small sample sizes and inconsistent methodologies for the performance and normalization of measurements, with few data on neonates. Some studies do reveal reproducible patterns in diastolic function in older children. A comprehensive pediatric nomogram of diastolic function involving a large population of normal infants and older children and using standardized methodology is warranted and would have tremendous impact in the care of children with acquired and congenital heart disease.

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

The aim of this article is to review the diagnostic and prognostic relevance of measurement of brain natriuretic peptide (BNP) and N-terminal pro-brain natriuretic peptide (NT-proBNP) in pediatric patients with heart failure caused by various acquired and congenital heart diseases (CHD). In January 2013, we performed a computerized literature search in the National Library of Medicine (PubMed access to MEDLINE citations; http://www.ncbi.nlm.nih.gov/PubMed/). The search strategy included a mix of Medical Subject Headings and free-text terms for the key concepts, starting from BNP assay and ‘NT-proBNP assay’, children, CHD. The search was further refined by adding the keywords neonate/s, newborn/s, heart failure, cardiomyopathy, screening, prognosis, follow-up, and management. BNP values are age and method dependent, even in pediatric populations. Regardless of age, there is great variability in BNP/NT-proBNP values within CHD characterized by different hemodynamic and clinical conditions. There is enough evidence to support the use of BNP/NT-proBNP as an adjunctive marker in the integrated evaluation of patients with congenital and acquired heart disease to help define severity and progression of heart failure as well in the monitoring of response to treatment. BNP/NT-proBNP can also be used for the screening of heart failure and as a prognostic marker in children undergoing cardiac surgery; however, to date, there are studies with heterogeneous patient groups, and diverse outcome measures selected are still few. BNP/NT-proBNP can be used as adjunctive markers in the integrated screening, diagnosis, management, and follow-up of children with heart failure caused by various acquired and congenital heart disease.

Diagnostic, prognostic and therapeutic relevance of B-type natriuretic hormone and related peptides in children with congenital heart diseases

Abstract The aim of this article is to review the diagnostic and prognostic relevance of measurement of brain natriuretic peptide (BNP) and N-terminal pro-brain natriuretic peptide (NT-proBNP) in pediatric patients with congenital cardiac diseases (CHD). A computerized literature search in the National Library of Medicine using the keywords “BNP assay” and “NT-proBNP assay”+neonate/s and newborn/s was performed. Next, we refined the analysis to include only the studies specifically designed to evaluate the clinical usefulness of BNP and NT-proBNP measurements in children with CHD. Several authors suggested that BNP/NT-proBNP is clinically helpful as a diagnostic and prognostic marker for children with suspected CHD. BNP values are age dependent, even in paediatric populations. Unfortunately, accurate reference values for BNP and NT-proBNP for neonatal ages have only recently become available. As a result, the lack of homogenous and accurate decisional levels in the neonatal period greatly limits the clinical impact of the BNP assay, and also contributed to the production of conflicting results. Regardless of age, there is great variability in BNP/NT-proBNP values among CHD characterized by different hemodynamic and clinical conditions. In particular, cardiac defects characterized by left ventricular volume and pressure overload usually show a higher BNP response than CHD which is characterized by right ventricular volume or pressure overload. BNP and NT-proBNP may be considered helpful markers in the integral clinical approach for patients with CHD. Measurement of BNP cannot replace cardiac imaging (including echocardiography, angiography and magnetic resonance), but provide independent, low cost and complementary information for the evaluation of cardiac function and clinical status.

Reference intervals for brain natriuretic peptide in healthy newborns and infants measured with an automated immunoassay platform

Abstract Background: In order to assess the reference intervals for B-type natriuretic hormone (BNP) in the first days of life, we measured peptide concentrations using the fully automated Access platform. Methods: Plasma BNP was measured in 188 apparently healthy newborns and infants throughout the first month of extra-uterine life, as well as in 245 healthy infants ranging from 1 month to 12 years of age. Results: BNP showed the highest concentrations in the first 2 days of life, with a progressive decline afterwards. Moreover, BNP values in the first week of life were significantly higher (p<0.0001) than values observed in the next periods. As a result, a significant negative correlation was found between BNP and age values when considering all 433 samples (ρ=–0.816, p<0.0001 by the Spearman rank correlation test). There was no significant difference between BNP values found in males and females. Conclusions: According to this data, our study indicates that at least two reference intervals should be used for newborns and infants. The first, with higher BNP values for neonates in the first week of extra-uterine life, and the other, with lower BNP values for infants aged 2 weeks to 12 years. Clin Chem Lab Med 2010;48:697–700.

Review and status report of pediatric left ventricular systolic strain and strain rate nomograms

Abstract Interest in strain (ε) and strain rate (SR) for the assessment of pediatric left ventricular (LV) myocardial function has increased. However, the strengths and limitations of published pediatric nomograms have not been critically evaluated. A literature search was conducted accessing the National Library of Medicine using the keywords myocardial velocity, strain, strain rate, pediatric, reference values, and nomograms. Adding the following keywords, the results were further refined: neonates, infants, adolescents, range/intervals, and speckle tracking. Ten published studies evaluating myocardial velocities, ε, or SR nomograms were analyzed. Sample sizes were limited in most of these studies, particularly in terms of neonates. Heterogeneous methods—tissue Doppler imaging, two- and three-dimensional speckle tracking—were used to perform and normalize measurements. Although most studies adjusted measurements for age, classification by specific age subgroups varied. Few studies addressed the relationships of ε and SR measurements to body size and heart rate. Data have been generally expressed by mean values and standard deviations; Z scores and percentiles that are commonly employed for pediatric echocardiographic quantification have been never used. Reference values for ε and SR were found to be reproducible in older children; however, they varied significantly in neonates and infants. Pediatric nomograms for LV ε and SR are limited by (a) small sample sizes, (b) inconsistent methodology used for derivation and normalization, and (c) scarcity of neonatal data. Some of the studies demonstrate reproducible patterns for systolic deformation in older children. There is need for comprehensive nomograms of myocardial ε and SR involving a large population of normal children obtained using standardized methodology.

Diagnostic role of magnetic resonance imaging in identifying aortic arch anomalies

PURPOSE The aim of this article was to assess the role of MRI in the diagnosis and management of a variety of complex aortic arch anomalies. MATERIALS AND METHODS Imaging was performed on a 1.5T Philips Gyroscan Intera. We retrospectively reviewed all cardiac MR scans performed from November 2003 to February 2007 at our institute to identify aortic arch anomalies. Magnetic resonance imaging included three-dimensional (3D) sagittal volume images, cine images, short axis ventricular volumes, phase contrast flow of great vessels, and 3D gadolinium magnetic resonance angiogram. RESULTS Three major categories of anomalies were identified in 47 patients: double aortic arch (n = 9), right-sided aortic arch with mirror image branching (n = 28), and aberrant right subclavian artery (n = 10). In the double aortic arch group, six patients were symptomatic, and four of them underwent a surgical division. Magnetic resonance imaging was used to plan the surgical management. In the other two groups, no patient presented with symptoms of airway or esophageal compression, and the arch abnormalities were noticed during investigation for other associated cardiac disease. However, we noticed a strong correlation with well-defined subgroups of congenital heart disease. Right-sided aortic arch was seen in patients with pulmonary atresia with ventricular septal defect (46.4%), tetralogy of Fallot (32.1%), and double outlet right ventricle with right atrial isomerism (14.2%). Seventy percent of the patients with aberrant right subclavian artery had aortic coarctation, and another case presented a complete aortic arch interruption. CONCLUSION Magnetic resonance imaging is an important diagnostic tool in identifying anomalies of the aortic arch and its branches and can be considered the imaging technique of choice when planning surgical management, especially when there are associated cardiac anomalies.

The combined use of neutrophil gelatinase-associated lipocalin and brain natriuretic peptide improves risk stratification in pediatric cardiac surgery.

Abstract Background: The aim of this study is to test the hypothesis whether the combined use of a cardio-specific biomarker, the brain natriuretic peptide (BNP) and a marker of early renal damage, the assay of urinary neutrophil gelatinase-associated lipocalin (uNGAL), may improve risk stratification in pediatric cardiac surgery. Methods: We prospectively enrolled 135 children [median age 7 (interquartile range 1–49) months] undergoing to cardiac surgery for congenital heart disease. All biomarkers were evaluated pre- and post-operatively at different times after cardiopulmonary-bypass (CPB): uNGAL at 2, 6 and 12 h; BNP at 12 and 36 h; serum creatinine at 2, 6, 12, and 36 h. Primary endpoints were development of acute kidney injury (AKI) (defined as 1.5 serum creatinine increase) and intubation time. Results: AKI occurred in 39% of patients (65% neonates and 32% older children, p=0.004). The peak of uNGAL values occurred more frequently at 2 h. uNGAL values at 2 h [median 28.2 (interquartile range 7.0–124.6) ng/L] had a good diagnostic accuracy for early diagnosis of AKI with an AUC (area under the curve) ROC (receiver operating characteristic) curve of 0.85 (SE 0.034). Using multivariable logistic regression analysis, development of AKI was significantly associated with uNGAL values at 2 h after CPB [OR=1.88 (1.30–2.72, p=0.001)], together with the CPB time and Aristotle score, as an index of complexity of the surgical procedure, while pre-operative BNP values were not. Furthermore, uNGAL and pre-operative BNP values (together with Aristotle score) were significantly associated with adverse outcome (longer intubation time and mortality). Conclusions: Pre-operative BNP and uNGAL values after surgery (together with the Aristotle score) were independently associated with a more severe course and worse outcome in children undergoing cardiac surgery for congenital heart disease.

Diagnostic accuracy of B-type natriuretic hormone for congenital heart disease in the first month of life

Abstract Background: The goal of the present study was to evaluate the diagnostic accuracy of B-type natriuretic hormone (BNP) assay in children with congenital heart disease (CHD) in the first month of life. Methods: BNP was measured in 152 neonates with CHD; 154 healthy children matched for age were used as controls. BNP was measured with a fully automated platform (Triage BNP reagents, Access Immunoassay Systems, Beckman Coulter, Inc., Fullerton, CA, USA). Results: BNP values were significantly higher (p<0.0001) in newborns and infants with CHD compared with control (CHD patients: median 1167.5 ng/L, range 25–54,447 ng/L; healthy children: median 150.5 ng/L, range 5–866 ng/L). The diagnostic accuracy of BNP was assessed using the receiver operating characteristic (ROC) analysis, taking into account the three different groups divided according to age. Group 1: all CHD patients and healthy newborns and infants as a whole (i.e., from birth to the 30th day of life); Group 2: from the 1st to 3rd day of life; Group 3: from the 4th to 30th day of life. The area under the curve (AUC) of the ROC curve for Group 3 (0.935) was significantly higher than that for Group 1 (0.843, p=0.009) and Group 2 (0.769, p=0.0003), while the AUC values of Group 1 and Group 2 were not significantly different (p=0.191). Conclusions: BNP may be considered a useful marker for screening in the integrated approach of newborns, infants and children with suspected CHD. However, the accuracy of the BNP assay varies greatly during the first month of extra-uterine life, showing the lowest diagnostic accuracy in the first 3 days after birth. After the second week of life, the biomarker becomes more accurate in ruling in CHD. Clin Chem Lab Med 2010;48:1333–8.

Reference values for plasma B-type natriuretic peptide in the first days of life.

The clinical relevance of B-type natriuretic peptide (BNP)1 and the amino terminal fragment of its prohormone (NT-proBNP) as biomarkers in pediatric heart disease have recently been shown (1)(2). BNP and NT-proBNP concentrations are dependent on age and sex, at least in adults(3). Because commercial methods are affected differently by the presence in plasma of several peptides derived from the degradation of intact prohormone and BNP(3), little if any agreement exists among reported reference intervals, especially those used for infants during the first days of extrauterine life(1). Data are scarce regarding the reference values for BNP and NT-proBNP in infancy (1)(2)(4). Recently, Nir et al.(2) summarized NT-proBNP concentrations measured with an electrochemiluminescence immunoassay method in 690 healthy individuals (47% males) with ages ranging from birth to 18 years, including 127 newborns in the first week of life (43 in the first 2 days). The NT-proBNP concentrations were highest in the first days of life, and then showed a marked decline. Concentrations in males and females differed only for children age 10–14 years. Large reference value studies for BNP for newborns and infants have …

Controversies in the definition and management of insignificant left-to-right shunts

Haemodynamically insignificant left-to-right shunts are frequently discovered when screening for congenital heart disease, resulting in significant economic and psychosocial impact. A literature search was performed within the National Library of Medicine using the keywords small/insignificant/silent atrial septal defect (ASD), ventricular septal defect (VSD), patent ductus arteriosus (PDA) and patent foramen ovale (PFO). The search was refined by adding the keywords definition, classification and follow-up. Our analysis revealed significant heterogeneity in the evaluation and management of innocent left-to-right shunts. The definitions for small defects vary greatly, making it difficult to distinguish between physiologic and pathologic lesions (eg, a PFO vs a true ASD). Most small defects will partially or completely resolve spontaneously early in life. If spontaneous resolution does not occur, the risk for long-term complications (such as embolic events and endocarditis) is low but poses several practical and ethical issues: immediate discharge versus long-term follow-up, duration and frequency of follow-up, and content and method of discussions with the parents. Additionally, there is controversy pertaining to treatment for PDAs and VSDs, particularly among interventional cardiologists, even though risk/benefit analyses are lacking. Standards and guidelines using consensus opinion for the management of insignificant left-to-right shunts are needed to address the heterogeneity in diagnosis and management as well as use of resources, ethical and psychosocial issues.