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The relationship between BNP, NTproBNP and echocardiographic measurements of systemic blood flow in very preterm infants

Abstract

Objective:

Preterm infants are at risk of circulatory compromise following birth. Functional neonatal echocardiography including superior vena cava (SVC) flow is increasingly used in neonatal medicine, and low SVC flow has been associated with adverse outcome. However, echocardiography is not readily available in many neonatal units and B-type natriuretic peptides (BNPs) may be useful in guiding further cardiovascular assessment. This study investigated the relationship between BNP, N-terminal pro-BNP (NTproBNP) and echocardiographic measurements of systemic blood flow in very preterm infants.

Study Design:

This is a prospective observational study. Sixty preterm infants <32 weeks gestational age were included after the treating neonatologist had requested an echocardiogram for suspected cardiovascular compromise. BNP and NTproBNP were sampled just before the echocardiogram. Echocardiographic examination included fractional shortening (FS), SVC flow, left and right ventricular output (LVO and RVO). Statistical analysis included simple linear regression of BNP and NTproBNP with echocardiographic measures and multiple regression including potential confounding variables.

Result:

Mean (s.d.) gestational age at birth was 275 (21) weeks, median (interquartile range, IQR) birth weight was 995 (845 to 1175) grams. Neither BNP nor NTproBNP correlated with SVC flow (BNP 95% confidence interval (CI) −0.0014 to 0.013, P=0.12; NTproBNP 95% CI −0.00069 to 0.01, P=0.085); LVO (BNP 95% CI −0.00078 to 0.0072, P=0.11; NTproBNP 95% CI −0.0034 to 0.0034, P=0.99); RVO (BNP 95% CI −0.00066 to 0.0058, P=0.12; NTproBNP 95% CI −0.0012 to 0.0044, P=0.25); or FS (BNP 95% CI −0.053 to 0.051, P=0.96; NTproBNP 95% CI −0.061 to 0.019, P=0.3). Multivariate linear regression did not significantly alter results.

Conclusion:

In this cohort of very preterm infants, BNP and NTproBNP did not correlate with echocardiographic measurements of systemic blood flow within the first 72 h of life.

Introduction

The transitional circulation of the newborn represents a unique situation to the clinician. The assessment of the circulatory status of the very preterm infant is particularly challenging as invasive cardiovascular monitoring is not available in this population, with the exception of arterial blood pressure monitoring. Clinical observation remains the mainstay of circulatory assessment, with some laboratory parameters such as acid base status and serum lactate adding additional information. In recent years, the use of functional echocardiography has increased in neonatal intensive care units (NICUs).1, 2, 3 Kluckow and Evans4 introduced the measurement of superior vena cava (SVC) flow as a surrogate for systemic blood flow in very preterm infants. They demonstrated that low SVC flow correlates with intraventricular hemorrhage (IVH) and impaired neurodevelopmental outcome at 3 years of age.5, 6 Other echocardiographic measurements such as right ventricular output (RVO) and left ventricular output (LVO) have been suggested for assessment of circulatory status in preterm infants.7 While the use of echocardiography is increasing in NICUs, it remains a modality that requires extensive experience to be performed reliably, considerable time allocation to conduct a study and it requires expensive equipment. Therefore, it is still not readily available in many NICUs worldwide and clinicians have to rely on clinical and biochemical markers of systemic blood flow.

B-type natriuretic peptide (BNP) and its inactive by-product N-terminal pro-BNP (NTproBNP) are synthesized in the cardiac ventricles in response to volume or pressure load.8 Several large studies in the adult population demonstrated the value of BNP and NTproBNP measurements in identifying patients with acute dyspnea of cardiac origin.9, 10, 11 In infants and children, BNP has shown to be a reliable test to diagnose structural and functional cardiovascular disease.12 BNP also supported risk stratification in patients with acute coronary syndromes and after myocardial infarction, predicted death and cardiovascular events in asymptomatic adults, sudden death in patients with chronic heart failure, mortality in acute decompensated heart failure, and postoperative complications and outcome in patients after heart surgery.13, 14, 15, 16, 17, 18

In the neonatal population, BNP is increased with hemodynamically significant left-to-right shunt in newborns with congenital heart disease.19 Both BNP and NTproBNP levels are elevated in newborns with pulmonary hypertension. Reynolds et al.20 measured BNP in term newborns with persistent pulmonary hypertension of the newborn. BNP levels were significantly higher in infants with persistent pulmonary hypertension of the newborn, but not in infants with respiratory disease or control infants. NTproBNP was shown to be significantly higher in infants with pulmonary hypertension secondary to congenital diaphragmatic hernia when compared with age-matched controls.21

In preterm neonates, research into BNP and NTproBNP has mainly focused on the diagnosis and management of the patent ductus arteriosus (PDA). Numerous studies have shown good correlation of BNP and NTproBNP levels and the hemodynamic significance of the PDA, as well as response to successful PDA treatment.22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33 Recent studies in preterm infants suggested that NTproBNP is a marker of bronchopulmonary dysplasia and urinary NTproBNP is a predictor of severe retinopathy of prematurity.34, 35

The aim of this study was to investigate whether BNP and NTproBNP measurements correlate with echocardiographic measurements of systemic blood flow in very preterm infants. We hypothesized that BNP and NTproBNP would predict compromised systemic blood flow as assessed by contemporary echocardiographic parameters.

Methods

Setting

This prospective observational study was conducted over a two and a half year period in the NICU at the Mercy Hospital for Women, a tertiary perinatal center in Melbourne, Australia, with 6000 births per year and 180 very low birth weight infants admitted to the NICU per year. The study was approved by the institutional human research ethics committee (Mercy Health, Melbourne, VIC, Australia). Written informed consent was obtained from the parents of enrolled infants before the study procedure.

Patients

Preterm infants born <32 weeks gestational age, admitted to the NICU and with an indwelling arterial catheter were eligible if the treating neonatologist requested an echocardiogram to assess systemic blood flow of the infant within the first 72 h of life. Infants with major cardiopulmonary anomalies and infants with suspected inborn errors of metabolism were excluded.

Data collection

Data collection included baseline, clinical management and outcome data. Data are collected prospectively in real time into the departmental database. All data were retrieved from this database and cross-checked with the medical file of each participant.

Study procedure

Once the treating consultant neonatologist requested an echocardiogram for an eligible patient, parents were approached and informed written consent was obtained. Arterial blood samples for BNP and NTproBNP analysis were taken from an indwelling arterial catheter (umbilical arterial catheter or peripheral arterial line) immediately before commencement of the echocardiogram study. Blood samples were transported to the central laboratory at room temperature without delay where they were immediately centrifuged and plasma and serum frozen at −80° C until assayed.

BNP and NTproBNP laboratory analysis

The BNP assay is a chemiluminescent microparticle immunoassay and samples were analyzed on an Abbott ARCHITECT analyser (Abbott Diagnostics Division, North Ryde, NSW, Australia). The NTproBNP samples were run on the Roche Cobas E170 analyser using the Elecsys electrochemiluminescence immunoassay proBNP II assay (Roche Diagnostics Australia Pty Limited, Castle Hill, NSW, Australia). Laboratory staff was blinded to all clinical details. All samples for BNP and NTproBNP analysis were batched and analyzed following completion of recruitment at the end of the study, hence results were not available for the treating neonatologists of the infants.

Echocardiography assessment

Our NICU employs a part-time (four half days a week) single experienced sonographer (SMD) to perform all neonatal echocardiograms including all echocardiograms conducted for this study. An after-hours service is provided for emergency situations. A Philips HD 11 XE ultrasound scanner and a S12-4 sector array transducer (Philips Medical, Eindhoven, The Netherlands) were used for all study echocardiograms. Fractional shortening (FS) was measured in M-mode as previously described by Sahn et al.36 SVC flow, RVO and LVO were performed as described by Evans and Kluckow.4, 7 All echocardiograms were reviewed by a consultant pediatric cardiologist blinded to the study.

Statistical analysis

BNP and NTproBNP were log transformed to obtain a normal distribution for analysis. Simple linear regression was used to investigate the relationship between the log-transformed BNP and NTproBNP respectively and echocardiography parameters of interest. The following potential confounders were tested for association with BNP or NTproBNP: gestation, birth weight, mode of delivery, 5 min Apgar score, surfactant administration, inotropes at the time of study, hour of life at study and the presence and the size of PDA. Potential confounders were included in the multivariate model if they were significantly related (P<0.05). Only hour of life at study and the size of PDA were significantly associated with BNP and NTproBNP. These were included in a multiple linear regression model. Regression diagnostics were conducted to test normality of residuals. Stata 11.2 (StataCorp, College Station, TX, USA) was used for all statistical analyses.

Results

Patients and clinical outcomes

A total of 60 preterm infants with a mean (s.d.) gestational age of 275 (21) weeks and a median (interquartile range, IQR) birth weight 995 (845 to 1175) grams were included. Median (IQR) time of measurement was 28 (16 to 49) hours. All infants required ventilatory support for respiratory distress syndrome at the time of the study: 44 (73.3%) infants received mechanical ventilation and 16 (26.7%) were managed on continuous positive airway pressure. Table 1 displays patient baseline characteristics and clinical outcomes.

Table 1 Patient baseline characteristics and clinical outcomes

BNP and NTproBNP results

All infants had NTproBNP analysis performed. Four infants’ blood samples could not be analyzed for BNP due to insufficient volumes. Median (IQR) BNP level was 424 (172 to 1288) pg ml−1. Median (IQR) NTproBNP level was 10 104.5 (5917.5 to 36 076.5) pg ml−1.

Median (IQR) BNP levels were 274 (143 to 601) pg ml−1 at 1 to 24 h, 1016 (461 to 2586) pg ml−1 at 25 to 48 h and 443 (115 to 1707) pg ml−1 at 49 to 72 h. Median (IQR) NTproBNP levels were 7553 (5339 to 11 328.5) pg ml−1 at 1 to 24 h, 19 464.5 (10 659.5 to 49 240.5) pg ml−1 at 25 to 48 h, and 14 815 (3613 to 42 108) pg ml−1 at 49 to 72 h.

Echocardiography results

All except one infant (ultrasound scanner breakdown) had an echocardiogram performed immediately following study blood sampling. Four infants were very unstable and had only a limited echocardiogram including SVC flow and FS but not LVO and RVO measurements. Forty-seven infants had a hemodynamically significant PDA with a diameter of 1.5 mm at the time of the study. Mean (s.d.) SVC flow was 127 (52) ml kg−1 per minute. Median (IQR) LVO was 135 (96 to 200) ml kg−1 per minute, and median (IQR) RVO was 237 (195 to 300) ml kg−1 per minute. Mean (s.d.) fraction shortening was 38 (7.5)%.

Correlation of BNP and NT-proBNP with echocardiography parameters of systemic blood flow

Table 2 shows simple linear regression analysis results for BNP and NTproBNP. Figures 1 and 2 display the relationship of BNP and NTproBNP levels to SVC flow. Multivariate linear regression analysis did not alter results or significance levels (Table 3).

Table 2 Simple linear regression analysis for log of BNP and NTproBNP and echocardiography parameters
Figure 1
figure1

Correlation between B-type natriuretic peptide (BNP) and superior vena cava (SVC) flow.

Figure 2
figure2

Correlation between N-terminal pro-B-type natriuretic peptide (NTproBNP) and superior vena cava (SVC) flow.

Table 3 Multiple linear regression analysisa for log of BNP and NTproBNP and echocardiography parameters

Discussion

Our study did not show any correlation between BNP or NTproBNP and echocardiographic parameters of systemic flow in a cohort of very preterm infants in the NICU. While disappointing, there are several reasons that may explain the failure of BNP and NTproBNP to guide further diagnostic assessment of circulatory status and requests for functional neonatal echocardiography.

BNP and NTproBNP are markers of volume or pressure load of the heart.8 The newborn transitional circulatory physiology is characterized by significant changes within minutes following birth.37 These hemodynamic changes are reflected in both BNP and NTproBNP levels rising sharply within the first 2 days before they show a steady decline. Cantinotti et al.38 demonstrated this for BNP in a cohort of 188 healthy newborns. Similarly, da Graca et al.39 showed the decline of BNP levels from day 3 of life in a cohort of preterm infants born less than 32 weeks gestational age. Mannarino et al.40 confirmed these findings in their study of preterm and term newborns analyzing BNP samples taken from cord blood and on the day of birth, day 3 and day 30.40 For NTproBNP, Mir et al.41 reported a similar picture in term newborns with initial high levels and a decline from day 3 of life. Other groups demonstrated this in the preterm population.26, 28, 42 In line with the literature, both BNP and NTproBNP levels in our study cohort increased within the first 48 h, and commenced declining between 49 and 72 h. Interpretation of high levels as potentially pathological is therefore difficult in the newborn population in this crucial time period following birth. Furthermore, the occurrence of a hemodynamically significant PDA can result in persistent high levels of BNP and NTproBNP. Flynn et al.24 demonstrated that BNP and PDA size do not correlate within the first 2 days of life but show a significant correlation beyond 2 days. We accounted for potential confounding in multiple linear regression analysis, however, age at the time of study and the presence or the size of PDA did not impact on the results of the study.

Our results are similar to those of El-Khuffash et al.'s43 study. In their cohort of 80 preterm infants with a median gestational age of 28 weeks, neither LVO nor RVO correlated with NTproBNP. In contrast to our study, they found a significant negative correlation between NTproBNP and FS. The study differed slightly to our study as all echocardiograms were performed at 12 h of age, whereas in this study echocardiograms were done upon request by the treating neonatologist, and infants within the first 72 h of life were included. In another study by El-Khuffash et al.26 including 131 echocardiograms in 48 preterm infants, no correlation between NTproBNP and FS was seen. Flynn et al.24 studied paired BNP and FS measurements in preterm infants, and Mannarino et al.44 studied BNP levels and FS in a cohort of preterm and term infants. Similar to this study, no correlation was found. It should be taken into consideration that the usefulness of FS in newborns has been questioned previously as an unreliable marker of systolic left ventricular function in newborns given the physiologic changes in the first days of life.26

SVC flow has been suggested as a non-invasive surrogate marker of systemic blood flow, and low SVC flow has been associated with IVH in prospective trials.5, 45, 46 To the best of our knowledge, this is the first study to assess the potential relationship between SVC flow and BNP and NTproBNP, respectively. We were unable to detect a significant correlation between SVC flow and BNP or NTproBNP in this cohort, even after adjusting for numerous potential confounders. SVC flow is a measurement of upper body blood flow returning to the heart. Being a marker of a flow state, SVC flow is probably to some degree independent from volume and/or pressure loading of the ventricles. Also, the preterm neonate does not per se suffer from ventricular dysfunction while it is undergoing significant physiologic circulatory changes in the transitional period. In this unique situation, high natriuretic peptide levels appear to reflect physiologic adaptation rather than major cardiac pathology in most patients.

It is acknowledged that several studies investigating BNP and NTproBNP and echocardiographic measurements of regional blood flow found significant relationships. Flynn et al.24 studied BNP and measurements of the diastolic runoff from descending aorta and superior mesenteric artery in a cohort of 20 preterm infants and found a significant correlation. El-Khuffash et al.26 demonstrated that NTproBNP and the descending aorta end-diastolic velocity significantly correlated in their study in 48 preterm infants. Buddhe et al.47 showed a significant correlation between NTproBNP levels and the pulsatility index in the superior mesenteric artery in 69 very low birth weight infants. For our study, we opted for measurements of SVC flow, LVO and RVO because these measurements have been performed in our NICU for many years. We also feel that SVC flow is currently the best studied echocardiographic surrogate measurement of systemic blood flow, and better reflecting cerebral blood flow than measurements in the descending aorta and SMA.

Our study has several strengths. It reflects a real life setting where echocardiography is not available on site around the clock. Therefore, the negative results can be taken into consideration by NICUs in a similar situation discussing the introduction of BNP or NTproBNP into clinical routine practice. We were able to eliminate inter-observer variability by using one single sonographer to perform all echocardiograms. All blood samples were immediately transported to the laboratory, and processed by the same scientist for all samples.

There are limitations. The study population is a selected cohort as we only included preterm infants with arterial access. This excluded a large proportion of babies deemed well enough not to require frequent arterial blood sampling or invasive blood pressure monitoring. Also, infants were only recruited when the treating neonatologist requested an echocardiogram, adding another layer of patient selection. There is obviously a degree of variability in defining the individual need for echocardiographic assessment. However as explained above it was the aim of our study to reflect a real life setting. We only included infants within the first 72 h of life. In contrast to our results, there may be a correlation between BNP/NTproBNP and echocardiographic markers of systemic blood flow beyond the first 72 h. We believe that this would be very challenging to investigate as most infants recover from early postnatal, transitional circulatory compromise within the first 2 to 3 days of life. Finally, the moderate sample size may have affected the results although this seems not very likely, given the lack of correlation in all studied measurements.

We conclude that in this cohort, BNP and NTproBNP did not correlate with echocardiographic measurements of systemic blood flow. On the basis of these data, BNP and NTproBNP do not appear useful in estimating the need for echocardiographic assessment of circulatory status in preterm infants in the first 72 h of life. Functional neonatal echocardiography remains the essential diagnostic modality to assess circulatory status in very preterm infants.

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Acknowledgements

We would like to thank all the families for their participation in this trial, all NICU nurses and Dr Clare Collins, Mercy Hospital for Women, and Jennifer Horvath (Austin Pathology, Melbourne, Australia) for their support. We gratefully acknowledge The Medical Research Foundation for Women and Babies, East Melbourne, Australia, for supporting this study. The Foundation had no involvement in study design, collection, analysis, and interpretation of data, writing and submission of the manuscript.

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Correspondence to K König.

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König, K., Guy, K., Walsh, G. et al. The relationship between BNP, NTproBNP and echocardiographic measurements of systemic blood flow in very preterm infants. J Perinatol 34, 296–300 (2014). https://doi.org/10.1038/jp.2014.2

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Keywords

  • prematurity
  • newborn
  • natriuretic peptides
  • circulatory compromise
  • neonatal functional echocardiography

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