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 Table of Contents  
ORIGINAL ARTICLE
Year : 2017  |  Volume : 30  |  Issue : 1  |  Page : 11-16

Role of brain-type natriuretic peptide in rapid diagnosis and prognosis of persistent pulmonary hypertension of the newborn


1 Department of Pediatrics, Faculty of Medicine, Alexandria University, Alexandria, Egypt
2 Department of Clinical and Chemical Pathology, Faculty of Medicine, Alexandria University, Alexandria, Egypt

Date of Submission04-Mar-2017
Date of Acceptance15-Mar-2017
Date of Web Publication12-Jul-2017

Correspondence Address:
Bahaa S Hammad
Department of Pediatrics, Faculty of Medicine, Alexandria University, Alexandria, 01666
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/AJOP.AJOP_3_17

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  Abstract 

Objective The diagnosis of persistent pulmonary hypertension of the newborn (PPHN) can often be difficult to make, especially in a clinical setting in which pediatric echocardiography is not readily available. This study aims at investigating the value of plasma brain-type natriuretic peptide (BNP) level as a noninvasive test in the diagnosis, prognosis, and differentiation of PPHN from other respiratory diseases in newborns with respiratory distress (RD).
Patients and methods We used a prospective cohort study with three groups. One group was diagnosed with PPHN by clinical and echocardiographic criteria (PPHN group: n=20). The second group had been diagnosed with respiratory disease; however, PPHN was ruled out by having no evidence of elevated pulmonary pressure by echocardiography (RD group: n=20). The third group had no respiratory disease and was breathing room air (RA group: n=20). Plasma BNP levels were measured by Ray Bio BNP Enzyme Immunoassay Kit at study entry for all groups and upon recovery for PPHN cases.
Results There was no difference between groups regarding gestational age, postnatal age, sex, birth weight, and mode of delivery. Initial BNP levels (pg/ml) were significantly elevated in the PPHN group relative to both the RA and RD groups. There was no difference in the initial plasma BNP level between the RD and RA groups. Plasma BNP levels declined significantly in the PPHN group upon recovery. Plasma BNP levels correlated with the gradient of the tricuspid regurgitation jet and the mean pulmonary artery pressure. Plasma BNP levels were higher, although insignificant, in PPHN because of underdevelopment. The mean plasma BNP level in septic babies was higher; however, this was insignificant, still the number of cases was low (two cases).
Conclusion Plasma BNP levels were elevated in infants with PPHN but not in infants with other forms of RD. Follow-up plasma BNP level showed significant decline after recovery of PPHN cases. Elevated plasma BNP levels in term or near-term infants with RD should increase the suspicion of PPHN.

Keywords: B-ANP, diagnosis, PPHN, prognosis, neonatal


How to cite this article:
Abdel latif MT, Hammad BS, Mikhael NL, Elmirahem ME. Role of brain-type natriuretic peptide in rapid diagnosis and prognosis of persistent pulmonary hypertension of the newborn. Alex J Pediatr 2017;30:11-6

How to cite this URL:
Abdel latif MT, Hammad BS, Mikhael NL, Elmirahem ME. Role of brain-type natriuretic peptide in rapid diagnosis and prognosis of persistent pulmonary hypertension of the newborn. Alex J Pediatr [serial online] 2017 [cited 2018 Oct 17];30:11-6. Available from: http://www.ajp.eg.net/text.asp?2017/30/1/11/210439


  Introduction Top


Persistent pulmonary hypertension (PPHN) is a disease of term and near-term newborns in which the pulmonary vascular resistance remains elevated during the neonatal period. The clinical presentation often resembles other cardiorespiratory diseases. Therefore, it is often difficult to make the correct diagnosis rapidly, which can delay appropriate treatment. This is a problem particularly in neonatal ICUs with unavailable echocardiography or a skilled operator. A rapid noninvasive test that could diagnose PPHN from other cardiorespiratory conditions would be of great value for the early and appropriate management of this serious disease [1].

Brain-type natriuretic peptide (BNP) is a 32-amino-acid endogenous peptide hormone released from the ventricular myocardium in response to its wall stretch. It was first isolated from porcine brain extracts − hence its name. It is also present in human brain, but more concentrated in the ventricular myocytes [2].

BNP exerts its effects through interaction with high-affinity receptors on the surface of target cells. Binding to their receptors, BNP activates guanylyl cyclase, leading to an elevation in intracellular cyclic GMP, which as second messenger activates calcium (Ca2+)-activated and ATP-sensitive potassium (K+) channels, thus promoting vasorelaxation. In addition, BNP causes diuresis, natriuresis, arterial and venous vasodilatation, and it antagonizes the renin–angiotensin system. BNP is excreted after cleavage by membrane-bound neutral peptidase, which is found in the kidneys and vascular tree [3].

Actually, there are three main etiological types of PPHN, namely underdevelopment, maldevelopment, and maladaptation. The hypoplastic vasculature associated with underdevelopment of pulmonary arteries is encountered in congenital diaphragmatic hernia, pulmonary hypoplasia, oligohydramnios, and pleural effusion. In maldevelopment, the lung parenchyma is normal but the pulmonary vasculature is remodeled and characterized by increased smooth muscle cell thickness and distal extension of muscle to vessels that are usually nonmuscular. Causes include idiopathic or primary PPHN, chronic fetal hypoxia, and premature closure of the ductus arteriosus. Maladaptation occurs when the pulmonary vasculature is structurally normal but abnormally constricted because of lung parenchyma diseases such as meconium aspiration syndrome (MAS), respiratory distress (RD) syndrome, sepsis, and pneumonia [4],[5].


  Patients and methods Top


This study was conducted in the neonatal ICU of El Shatby Children Hospital. Newborn infants with RD suspected clinically to suffer from PPHN underwent an echocardiogram via HD, 11 XE machine with S8-3 probe (Philips, Yorba Linda, USA). Twenty of those fulfilling the criteria of PPHN were enrolled in the study (PPHN group). Twenty other RD infants lacking these ECHO criteria were included as well (RD group). Room air group (RA) included 20 age-matched neonates, term and near-term babies admitted to the neonatal ICU for indications other than RD. Newborns with cardiac diseases, congenital anomalies, or evident genetic anomalies were excluded. ECHO was repeated whenever deemed necessary and upon recovery of surviving PPHN infants.

Ethical approval for the study was obtained from the Ethical Review Committee, Alexandria University. Moreover, an informed written consent was obtained from the parents.

Full maternal history was taken including age, parity, gravidity, chronic illnesses, drug intake, mode of delivery, and time of rupture of membranes. All neonates were thoroughly examined − whenever their condition permits − and the gestation age, birth weight, postnatal age, and sex were determined.

Brain-type natriuretic peptide measurements

Plasma BNP levels were measured with commercially available competitive enzyme-linked immunoassay (RAY bio BNP enzyme immunoassay kit, Norcross, USA). Blood was collected from the infant at diagnosis (mean postnatal age 22 h) into standard blood sample collection vial with EDTA. Samples were centrifuged immediately and preserved at −20°C [6].

Statistical analysis

Data were fed to the computer and analyzed using IBM SPSS software package, version 20.0. Qualitative data were described using number and percent. Quantitative data were described using range (minimum and maximum), mean, SD, and median. Significance of the obtained results was judged at the 5% level. The used tests were χ2-test, Fisher’s exact or Monte Carlo correction, F-test (analysis of variance), post-hoc test (least significant difference), Mann–Whitney test, and Kruskal–Wallis test.


  Results Top


The demographic data of the studied groups showed that there was no significant difference as regards gestational age, postnatal age, sex, birth weight, and mode of delivery between the studied groups ([Table 1]).
Table 1 Demographic data of the studied groups

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[Table 2] and [Figure 1] show distribution of studied samples according to the probable etiological classification of PPHN, and they show that maladaptation type is the most common type 14 (70%) cases. MAS represented the most common cause, which composes 40% of the cases.
Table 2 Distribution of studied sample according to probable etiology of persistent pulmonary hypertension of the newborn (n=20)

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Figure 1 Pie of pie chart shows the probable etiology of PPHN – maladaptation forms 70% of cases and MAS is the most common cause. MAS, meconium aspiration syndrome; PPHN, persistent pulmonary hypertension of the newborn

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[Table 3] shows that the mean plasma BNP level was significantly higher in the PPHN group than in RD and RA groups.
Table 3 Brain-type natriuretic peptide level among different studied groups

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The mean plasma BNP level was measured among three types of PPHN. Underdevelopment type had the highest level, although insignificant ([Table 4]).
Table 4 Mean plasma brain-type natriuretic peptide level in subtypes of persistent pulmonary hypertension of the newborn

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Causes of maladaptation were classified into MAS (eight cases), pneumonia (four cases), and sepsis (two cases). Sepsis had the highest plasma BNP level; however, it was statistically insignificant ([Table 5]).
Table 5 Mean plasma brain-type natriuretic peptide level in the causes of maladaptation

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[Table 6] shows that PPHN cases were classified according to the velocity of tricuspid regurgitation jet into mild (n=5) and moderate to severe (n=15). Mean plasma BNP level was significantly higher in moderate to severe cases.
Table 6 Plasma brain-type natriuretic peptide level according to severity of persistent pulmonary hypertension of the newborn in terms of tricuspid regurgitation jet velocity (n=20)

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[Table 7] shows that PPHN cases were again classified into mild and moderate to severe in terms of pulmonary artery pressure (PAP). Mild cases were 4 (n=4). Moderate to severe cases were 16 (n=16). Plasma BNP was significantly higher in the moderate to severe group. Thus, the higher the PAP the greater the BNP level.
Table 7 Plasma brain-type natriuretic peptide level according to severity of persistent pulmonary hypertension of the newborn in terms of pulmonary artery pressure (n=20)

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[Table 8] shows that oxygenation index (OI) was measured in 13 mechanically ventilated PPHN cases. Accordingly, they were classified into mild (n=8) and moderate to severe (n=5). There was no significant correlation between OI and plasma BNP level.
Table 8 Plasma brain-type natriuretic peptide level according to severity of persistent pulmonary hypertension of the newborn in terms of oxygenation index (n=13)

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Among PPHN cases, 12 infants survived and eight died. Mean plasma BNP level was higher in the infants who died compared with those who survived, although not reaching a significant level ([Table 9]).
Table 9 Relation between mortality and plasma brain-type natriuretic peptide level in case group

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Plasma BNP level was measured initially at study entry and upon recovery of cases. Twelve infants with PPHN survived (n=12). Plasma BNP level was declined significantly after recovery ([Table 10]).
Table 10 Comparison between plasma brain-type natriuretic peptide level in persistent pulmonary hypertension of the newborn cases at study entry and after recovery of survived infants (n=12)

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  Discussion Top


The results of the present study showed no significant differences among the three studied groups regarding gestational age, postnatal age (h), sex, birth weight, and mode of delivery ([Table 1]).

The studied PPHN cases were distributed according to the probable etiology; two (10%) infants had the underdevelopment type attributed to oligohydramnios from premature rupture of membranes with amniotic fluid leak. Idiopathic PPHN due to maldevelopment was suspected in four (20%) infants. Fourteen (70%) infants had maladaptation PPHN. Among the latter, eight suffered from MAS, four from pneumonia, and two had culture proved sepsis ([Table 2] and [Figure 1]). The results of the present study showed that maladaptation PPHN due to MAS is the most frequent type. This was in agreement with Roofthooft et al. [7] who found maladaptation/maldevelopment as the underlying pathophysiological mechanism in majority of their studied patients. Konduri and Kim [8] and Nair and Lakshminrusimha [9] also reported MAS as the most common cause of PPHN.

The initial plasma BNP levels (pg/ml) were significantly higher in cases with documented PPHN compared with infants with other types of RD and neonates breathing RA. No significant difference was observed comparing babies on RA and RD infants not suffering from PPHN ([Table 3]). This was in agreement with Reynolds et al. [1].

Plasma BNP was compared between the three etiological types of PPHN. Underdevelopment type had the highest level, although the difference was insignificant ([Table 4]). This might be explained by sustained cardiac strains days before delivery. To the best of our knowledge, no previous studies tackled such comparison. Among maladaptation PPHN, surprisingly, the mean plasma BNP level of the two septic cases was higher than its levels in cases complicating MAS or pneumonia. No such finding was reported in the literature ([Table 5]).

To explore the validity of plasma BNP as a marker for the severity of PPHN, the cases were arbitrarily classified in terms of tricuspid regurgitation and PAP into mild group (five cases) and moderate to severe (15 cases). As shown in [Table 6] and [Table 7], the mean plasma BNP level was significantly higher in the latter group. Reynolds et al. [1] reported similar results as he noted a significant correlation between pressure gradient across Tricuspid valve and BNP levels. Nevertheless, further studies are needed to explore the relation between the severity of PPHN and plasma BNP level.{Table 7}

OI of the 13 infants on mechanical ventilation was calculated. Pursuing the study of Roofthooft et al. [7], the severity of PPHN was classified as mild less than 21.5, moderate and severe when the OI is less than 21.5, moderate to severe (21–40) ([Table 8]). This study found no correlation between plasma BNP level and OI. Vijlbrief et al. [10] and Shah et al. [11] reported similar results. On the other hand, Reynolds et al. [1] reported a significant, although quite weak, correlation.

In this work, the initial mean plasma BNP level in the eight infants with PPHN who died was higher, although insignificant, compared with that of those who recovered ([Table 9]). This relatively high level may be because of other confounding factors contributing to the demise of these infants. Thus, initial plasma BNP level in infants with PPHN is a useless predictor of mortality, although further studies are needed to confirm this assumption.

In this study, the mean plasma BNP level declined significantly in the 12 PPHN infants upon recovery ([Table 10]); this could be due to recovery of ventricular strain leading to decline of plasma BNP. In favor of this finding, Vijlbrief et al. [10] stated that BNP may be useful in evaluating the course and treatment of PPHN. They added that this biomarker could serve as a predictor of rebound PPHN during weaning or after cessation of inhaled nitric oxide [10]. Reynolds et al. [1] observed a progressive rise in BNP level in PPHN neonates with worsening respiratory status. The same workers observed that the initial BNP level almost tripled in deteriorating infants as PPHN became more aggressive [1]. In support of this latter observation, Baptista et al. [12] found that when congenital heart disease has been excluded, BNP can serve as a biomarker in the follow-up of treatment of PPHN.


  Conclusion Top


It could be concluded that plasma BNP is a quite useful biomarker to pin-point the diagnosis of PPHN in neonates with RD when echocardiography or skilled operator is unavailable. In addition, it could serve as an indicator of the severity of the disease. The scarcity of published data on the significance of this test in PPHN makes it mandatory to conduct further studies in this area.

Financial support and sponsorship

Nil.

Conflicts of interest

There is no conflict of interest.

 
  References Top

1.
Reynolds EW, Ellington JG, Vranicar M, Bada HS. Brain-type natriuretic peptide in the diagnosis and management of persistent pulmonary hypertension of the newborn. Pediatrics 2004; 114:1297–1304.  Back to cited text no. 1
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2.
Minamino N, Horio H, Nishikimi T. Natriuretic peptides in the cardiovascular system. In: Kastin AJ, editor. The handbook of biologically active peptides. 1st ed. New York; London: Academy Press; 2006: 1217–1225.  Back to cited text no. 2
    
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Price JM, Hellermann A. Inhibition of cGMP mediated relaxation in small rat coronary arteries by block of CA++ activated K+ channels. Life Sci 1997; 61:1185–1192.  Back to cited text no. 3
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Ostrea EM, Villanueva ET, Natarajan G, Uy HG. Persistent pulmonary hypertension of the newborn: pathogenesis, etiology, and management. Paediatr Drugs 2006; 8:179–188.  Back to cited text no. 4
    
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Steinhorn RH, Abman SH. Persistent pulmonary hypertension. In: Gleason CA, Devaskar SU. Avery’s diseases of the newborn, Ch 52. 9th ed. Philadelphia, PA: Elsevier Saunders; 2012: 732–740.  Back to cited text no. 5
    
6.
Zhengp P, Liu M. Study of relationship between BNP levels and heart function after open heart surgery in congenital heart disease. Zhongguo Wei Zhong Bing Ji Jiu Yi Xue 2012; 24:241–243.  Back to cited text no. 6
    
7.
Roofthooft MTR, Elema A, Bergman KA, Berger RM. Patient characteristics in persistent pulmonary hypertension of the newborn. Pulm Med 2011 2011:858154.  Back to cited text no. 7
    
8.
Konduri GG, Kim UO. Advances in the diagnosis and management of persistent pulmonary hypertension of the newborn. Pediatr Clin North Am 2009; 56:579–600.  Back to cited text no. 8
    
9.
Nair J, Lakshminrusimha S. Update on PPHN: mechanism and treatment. Semin Perinatol 2014; 38:78–91.  Back to cited text no. 9
    
10.
Vijlbrief DC, Benders MJ, Kemperman H et al. B-type natriuretic peptide and rebound during treatment for persistent pulmonary hypertension. J Pediatr 2012; 160:111–115.  Back to cited text no. 10
    
11.
Shah N, Natarajan G, Aggarwal S. B-type natriuretic peptide: biomarker of persistent pulmonary hypertension of the newborn? Am J Perinatol 2015; 32:1045–1049.  Back to cited text no. 11
    
12.
Baptista MJ, Correia-Pinto J, Rocha G, Guimaraes H, Areias JC. Brain type natriuretic peptide in the diagnosis and management of persistent pulmonary hypertension of the newborn. Pediatrics 2005; 115:1111.  Back to cited text no. 12
    


    Figures

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    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8], [Table 9], [Table 10]



 

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