N-terminal pro-brain natriuretic peptide used for screening hemodynamically significant patent ductus arteriosus in very low birth weight infants: How and when?

1 Introduction

Patent ductus arteriosus (PDA) on the 4th day of life would persist in approximately 10% of infants with gestational age (GA) between 30 and 37 weeks, in 80% of infants with GA between 25 and 28 weeks, and in 90% of preterms born at 24 weeks of GA [1]. However, among infants with birth weights of < 1,500 g (very low birth weight infants, VLBWIs), 85% needs treatment [2]. The prolonged condition of PDA in preterms can be associated with important complications, such as severe respiratory distress syndrome (RDS), prolonged need for assisted ventilation, pulmonary hemorrhage, bronchopulmonary dysplasia (BPD) [3], necrotizing enterocolitis (NEC), renal function damage, intraventricular hemorrhage (IVH), periventricular leukomalacia (PVL), cerebral palsy (CP), or death [4]. Meanwhile, in terms of the possibility of spontaneous closure of the ductus and side effects of treatments, and regardless of whether drugs were given or surgery was performed, the most reasonable strategy at present appears to be reserving treatment only for hemodynamically significant PDA (hsPDA) [5]. Although some studies suggested that the causative relationship between PDA and complications of prematurity [7], many infants with hsPDA have serious hemodynamical complications, so these infants must be diagnosed. Echocardiography remains as the diagnostic gold standard, but requires expensive equipment and the assistance of a trained operator, which is not available all the time in all neonatal units.

Brain natriuretic peptide (BNP) and amino-terminal pro-B-type natriuretic peptide (NTproBNP) are synthesized and released into the circulation by cardiac ventricular myocytes in response to pressure overload, volume expansion and increased myocardial wall stress. Within these myocytes, the precursor proBNP (108 amino acids) is converted to the biologically active form, BNP (77–108 amino acids), and the inactive NTproBNP fragment (1–76 amino acids), while NTproBNP has a longer half-life (60-120 minutes vs. 22 minutes), is more stable in vitro [8], and may serve as a better marker than BNP for assessing ventricular dysfunction and volume overload [9]. It is known that in hsPDA, significant shunting of blood occurs from the systemic to the pulmonary circuit, resulting in changes in pressure overload and myocardial wall stress. Therefore, subsequent studies have been conducted to prove that NTproBNP can be a useful biomarker for diagnosing hsPDA in premature neonates.

Recently, a systematic review [10], which included 11 NTproBNP studies, concluded that the sensitivity and specificity of NTproBNP for diagnosis of hsPDA was 90% (95% CI: 0.79–0.96) and 84% (95% CI: 0.77–0.90), respectively. However, these studies varied by methodological quality, type of commercial assay, thresholds, age at testing, gestational age, and whether an assay was used. Thus, there is presently no consensus on its optimal values and proper testing-time. The present prospective and blinded study was undertaken to establish a range of plasma NTproBNP concentrations found in VLBWIs suffering from PDA, and determine how and when to use these as a screening tool for predicting hsPDA.

2 Methods

In the present prospective study, results suggested that for infants with hsPDA, there was significant shunting of blood from the systemic circuit to the pulmonary circuit, resulting in increased pulmonary blood flow and the subsequent increased pressure overload and myocardial wall stress, as well as cardiac pressure (reflected by high pulmonary pressure). The changes in pressure were mainly decided by the volume of the shunt. Hence, there was a significant difference in NTproBNP value between the hsPDA group and asPDA group, indicating that NTproBNP level had a patent role in diagnosing hsPDA in infant with PDA.

As revealed in the successive monitoring of plasma NTproBNP concentration, the values in infants without hsPDA remained at a relatively stable and lower level in the first three days of life, which was similar to a plateau. For infants with hsPDA, these values rapidly and significantly increased within 24–48 hours of life, and remained high on within 48–72 hours of life. The peak levels presented on day two (24–48 hours of life), which is in accordance with the studies conducted by Alenazi [14] and Ramakrishnan [15], in which NTproBNP remained at a high level even on day seven. In general, in healthy preterm infants without hsPDA, the levels of NTpBNP would surge at birth, maintain a plateau on days 3–4, and rapidly decline within a week. Then, this would be followed by a steady fall to a stable level, reaching a constant level in infancy [14–16]. Since the preterm infants appears to have unstable hemodynamic changes in the first few days after birth, and it was assumed that these various influences would induce the DA to open or reopen, such as resuscitation, PS therapy and fluid therapy, with not a sole, but a comprehensive influence. Proper management would probably induce the DA to close or partly close by day three.

To date, studies of NTproBNP for the early prediction of hsPDA continue to have varying cutoff values and testing times (day two or three) [9, 14–18]. In order to discriminate whether the NTproBNP level on day two or three would be better, both values of these two days were taken into consideration. As a result, the NTproBNP level in the hsPDA group was significant higher than that in the control group, both on day two and day three. Preterm infants with NTproBNP levels exceeding 3,689.0 pmol/L on day two of life, and levels exceeding 2,331.5 pmol/L on day three of life were very likely to be diagnosed with hsPDA. Some recent studies were summarized with the present study in Table 4. All of these had the same assay (Roche Elecsys system) and a relatively similar GA. Furthermore, the thresholds widely varied from 1,203 pmol/L [16] to 7,252 pmol/L [14] on day two of life. The possible reasons would be that the conditions of these infants were more unstable and in need of various clinical management within the first 48 hours after birth, leading to more influences on circulation. However, on day three (48–72 hours), these findings appeared to be similar to that observed in the present study, to a certain extent. The scatter plot revealed a relatively concentrate trend, ranging from 1345.3 pmol/L [9] to 3196.8 pmol/L [18]. These variations may be due to the different populations (including races, GA, and BW) studied, the severity of illness, and the definition of hsPDA across these studies.

Moreover, the logistic regressive analysis revealed that NTproBNP level was an independent predictor for hsPDA, both on day one and day two. The NTproBNP level on day three was a dependent risk factor of hsPDA. Hence, it appears that day three of life (48–72 hours) would be the optimal testing time.

Traditional echocardiographic parameters, such as DA size and the LA:AO ratio, were used as the gold standard for determining hsPDA [14, 19]. In the present study, the same results were demonstrated, in which NTproBNP significantly correlated with the echo parameters of the DA size and LA/AO ratio, both on day two and day three of life (P < 0.05). However, when only infants with hsPDA were taken into consideration, no significant correlation between NTproBNP and the LA/AO ratio was found (P > 0.05). This was consistent with the study conducted by Harling S et al., which revealed that ductal diameter was the most accurate echocardiographic marker for predicting a significant shunt. In the preterms observed in studies conducted by Martinovicie et al. [21] and Buddhe et al. [22], there was a relatively stronger correlation between plasma NTproBNP level and DA size, when compared to the LA/AO ratio. Furthermore, the study conducted by König K et al. [23] also revealed that NTproBNP was only significantly correlated with PDA size in very preterm infants.

To date, the present prospective study and other studies have shown that early plasma NTproBNP levels in preterm infants can be used to predict the presence of hsPDA, and correlated this with the degree of ductal shunting through significant positive correlations with the DA size and LA/OA ratio. Plasma NTproBNP, which lacks the influence of antenatal and postnatal factors on these levels (gender, chorioamnionitis, steroids, delivery, and inotrope use) [9], has been proven to be a useful tool for predicting hsPDA and guiding the target treatment in the early stage [24, 25]. Concerning the more variable levels in the first 48 hours after birth, and acting as a dependent risk factor of hsPDA on day three (48–72 hours), it is recommended that the proper time to screen for hsPDA is 48–72 hours after birth.

The limitations of the present study were as follows. The study had a small sample size. In addition, there were few confounding factors that could influence the validity of the NTproBNP levels, such as increased pulmonary vascular resistance, concomitant renal impairment, hydration status and sepsis. And while BNP is positively associated with left to right shunt, currently there is no clear evidence that BNP can be used to determine treatment decisions. We also did not specifically statedthe treatment decisions regarding active ductal closure interventions, as we did not directly address whether there is a high predictive value of this test to identify infants who would benefit from intervention. In addition, Kulkarni MAA indicated that that BNP or NT-proBNP assays should be locally validated for specific patient population and outcomes, so we still need to validate the cutoff value detected in our local population, since the data may not reach the same value in other centers, so that our findings can be used as a reference for other medical centers.

The biomarker of plasma NTproBNP levels during the early neonatal period is significantly correlated to the PDA shunt magnitude. This can be applied as a useful tool to screen and assess hsPDA in premature infants, which is cost effective, easily available, and can supplement the information obtained from functional echocardiography, aiding in the management of hsPDA. NTproBNP levels of > 3,689.0 pmol/L on postnatal day two or > 2,331.5 pmol/L on postnatal day three indicate the high possibility of hsPDA in VLBWIs, with high sensitivity and specificity. However, the investigators proposes day three of life (48–72 hours) as the optimal testing time.