|Year : 2016 | Volume
| Issue : 3 | Page : 143-149
Gestational and postnatal age influence B-type natriuretic peptide level used in diagnosis of a hemodynamically significant patent ductus arteriosus in preterm infants
Kate A Tauber1, Evgenia Granina1, Robin M Doyle2, Upender K Munshi1
1 Department of Pediatrics, Albany Medical Center, Albany, NY 12208, USA
2 Capital District Pediatric Cardiology Associates, Albany, NY 12208, USA
|Date of Web Publication||28-Sep-2016|
Dr. Kate A Tauber
Albany Medical Center, Bernard and Millie Duker Children's Hospital, 47, New Scotland Avenue, MC101, Albany, NY 12208
Source of Support: None, Conflict of Interest: None
Clinical trial registration NCT01497054
Objective: To determine a cutoff value for B-type natriuretic peptide (BNP) level above which suggests a hemodynamically significant patent ductus arteriosus (hsPDA) and evaluate whether gestational age influences BNP production. Subjects and Methods: This was a prospective, observational study on infants of 24 0/7-31 6/7 weeks gestation. Up to 5 BNP levels were drawn within the first 2 weeks of life. An echocardiogram was done within the first 5 days in conjunction with the second BNP level. A patent ductus arteriosus (PDA) was graded as no, nonsignificant, or hemodynamically significant. Kruskal-Wallis test and Mann-Whitney U-test were used for statistical analyses. Result: There were 135 BNP-echocardiogram pairs in 95 patients. BNP levels were significantly different between PDA groups, P < 0.0001. Based on our receiver operating characteristic curve, a BNP level of 276 pg/ml or above on the day of life (DOL) 5 was suggestive of an hsPDA. Gestational age had a significant effect on BNP production. Conclusion: A cutoff BNP level of 276 pg/ml on DOL 5 is suggestive of an hsPDA in preterm infants of <32 weeks gestation. Gestational age has a significant impact on the ability of a preterm infant to produce BNP in response to an hsPDA, and therefore, different cutoff values based on gestational age may be appropriate.
Keywords: B-type natriuretic peptide, neonate, patent ductus arteriosus
|How to cite this article:|
Tauber KA, Granina E, Doyle RM, Munshi UK. Gestational and postnatal age influence B-type natriuretic peptide level used in diagnosis of a hemodynamically significant patent ductus arteriosus in preterm infants. J Clin Neonatol 2016;5:143-9
|How to cite this URL:|
Tauber KA, Granina E, Doyle RM, Munshi UK. Gestational and postnatal age influence B-type natriuretic peptide level used in diagnosis of a hemodynamically significant patent ductus arteriosus in preterm infants. J Clin Neonatol [serial online] 2016 [cited 2019 Dec 9];5:143-9. Available from: http://www.jcnonweb.com/text.asp?2016/5/3/143/191241
| Introduction|| |
A patent ductus arteriosus (PDA) is a common occurrence in preterm infants, especially those of <28 weeks gestation., A hemodynamically significant PDA (hsPDA) can be a cause of significant morbidity and has been associated with chronic lung disease, pulmonary hemorrhage, renal hypoperfusion, and necrotizing enterocolitis.,,, However, not all PDAs are hemodynamically significant and require treatment.
The gold standard to determine whether an infant has an hsPDA is to perform an echocardiogram. This requires that centers have access to cardiologists to perform and analyze such studies. A simple biomarker that could help diagnose an hsPDA would be extremely helpful, especially in community centers that do not have routine access to cardiology services. Over the past decade, researchers have focused on B-type natriuretic peptide (BNP) as a possible biomarker. BNP is mainly synthesized in the ventricles of the heart and released in response to ventricular wall stress due to volume and pressure loading., Since one of the hallmarks of hsPDA is left ventricular wall stress, it seems logical to assume that you would see an elevation in BNP level in infants with hsPDA. However, the conclusions from the studies thus far have shown a wide range of BNP levels in infants with hsPDA.,,,,,,,,, This variability could be due, in part, to the small numbers of patients included in these studies, the varying gestational ages, and the timing of when the BNP levels were measured. Other comorbidities that lead to ventricular wall stress such as pulmonary hypertension and infection have been implicated to cause elevated BNP levels and may have also played a role the variability seen in previously published data.,
Although prior research has shown that BNP levels are elevated in preterm infants with hsPDA, none have specifically addressed whether the degree of prematurity has an effect on BNP production. It is known that immature cardiomyocytes in preterm infants behave differently than in term infants.,,, The preterm myocardium is less mature, with fewer mitochondria, less energy stores, decreased number of myofibrils, which are also not well organized, all leading to a decreased ability to respond to stresses in the postnatal period. We hypothesized from this information that the more immature the infant, the less able they would be to produce BNP in response ventricular wall stress.
This study was undertaken to determine a BNP cutoff value which suggests the presence of an hsPDA and to determine whether this value changes based on gestational age.
| Subjects and Methods|| |
This was an Institutional Review Board approved, prospective, clinical study conducted in the Neonatal Intensive Care Unit. Infants were enrolled from November 2011 to April 2013. Parents of infants who were born at 24 0/7-31 6/7 weeks gestation were approached for consent within 24 h after delivery. Infants were excluded from the study if they were treated for sepsis or meningitis, had a congenital heart defect, had significant perinatal depression that required chest compressions, or had evidence of pulmonary hypertension on echocardiogram.
BNP samples were collected within 24 h of birth (considered day of life [DOL] 1), on DOL 5, DOL 10, and DOL 15. If there was clinical concern for a PDA and the medical team requested an echocardiogram, then a BNP level was drawn on the same day the echocardiogram was performed. If the infant was treated for an hsPDA, then a repeat BNP level was performed at the end of treatment on the same day as the follow-up echocardiogram. If there was no clinical concern for an hsPDA, then an echocardiogram was performed on DOL 5 as part of the study. Up to a total of five BNP levels could be drawn within the first 2 weeks of life. A sincere effort was made to coordinate study BNP levels with routine laboratories to minimize draws specifically for study purposes.
Measurement of B-type natriuretic peptide levels
BNP levels were measured using 250 μl of whole blood on a commercially available point of care meter (Triage BNP Assay, Alere, Inc., Waltham, MA, USA). The blood was collected in lavender top ethylene diamine tetra-acetic acid tubes and run according to the manufacturer's instructions. The Triage assay works by initially separating the blood cells from the plasma by a filter. Then, the plasma enters a reaction chamber that contains murine polyclonal fluorescence-tagged BNP antibodies. After 2 min of incubation time, capillary action results in migration of the reaction mixture through the diagnostic lane to a zone of immobilized murine monoclonal antibody against the ring structure of BNP, binding the BNP fluorescent antibody complex. The unbound fluorescent antibodies were washed away by excess plasma. The Triage BNP device quantifies the fluorescence intensity of the BNP assay zone using an internal calibration curve. The measurable range of BNP values using this assay is 5-5000 pg/ml. The entire process takes about 15 min. BNP samples were run by the study team (comprised the authors of this paper), and the results were not known to the medical team (comprised the neonatal attending, nurse practitioners, and residents caring for the patient).
All study participants underwent at least one echocardiogram. If the medical team was concerned for an hsPDA, they could ask for one at any time; however, if one had not been done by DOL 5, then an echocardiogram was done on that day as part of the study. Echocardiograms were also done after medical treatment for an hsPDA. All echocardiogram results that had a BNP level done on the same day were included in the statistical analysis. Results of the echocardiograms done solely as part of the study were not revealed to the medical team unless a congenital defect was found that would require medical intervention or subsequent follow-up. Echocardiograms were performed at the bedside by 1 of 5 pediatric cardiologists using an Acuson Sequoia C512 Echocardiographic Scanner (Malvern, PA, USA). All echocardiograms were reviewed at the end of the study by a single cardiologist who was blinded not only to the BNP levels but also to whether the infants had been diagnosed and/or treated for PDA. The ductus was graded by the reviewing cardiologist as either closed (no), nonsignificant PDA (nsPDA), or hsPDA taking into consideration the LA: AO ratio, the ductal diameter, and the flow pattern through the PDA.
The statistical analyses were performed using GraphPad Prism version 5.04 (GraphPad Software, San Diego, California, USA). The data failed the D'Agostino and Pearson normality test, and therefore, nonparametric statistical analyses were performed. The Kruskal-Wallis test was used to determine whether there was a difference in BNP level between grades of PDA, and the Mann-Whitney U-test was used in all other analyses. The receiver operating characteristic (ROC) curves were created to find a cutoff value for BNP that would give the optimal sensitivity and specificity. All BNP levels are expressed as median with the interquartile (IQ) range.
| Results|| |
A total of 169 preterm infants ranging in gestational age from 24 0/7 to 31 6/7 weeks gestation were admitted during the study period. Consent was obtained for 109 of those eligible infants (64%) and 95 infants ultimately had data to analyze. [Table 1] shows the demographic information of infants, and [Figure 1] shows the flow diagram of study participants. There was a significant difference in gestational age and birth weight between the no PDA group and the nsPDA and hsPDA groups, but no significant difference between the nsPDA and hsPDA groups.
|Figure 1: Flow of recruitment of study participants. ASD - Atrial septal defect; VSD - Ventricular septal defect; DOL - Day of life; DR - Delivery room|
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|Table 1: Demographics of study infants based on patent ductus arteriosus size on first echo |
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B-type natriuretic peptide levels and patent ductus arteriosus
There were a total of 135 BNP-echocardiography pairs from the 95 infants included in the analysis. A PDA was categorized as either no PDA, nsPDA, or hsPDA by the reviewing cardiologist. Analysis of the BNP-echocardiogram pairs from all the preterm infants showed that the BNP level drawn on the same day as the first echocardiogram correlated positively with PDA grade [P < 0.0001, [Figure 2]. Median BNP level for the no PDA group was 18 pg/ml (IQ: 8-36 pg/ml), median BNP level for the nsPDA group was 50 pg/ml (IQ: 25-272 pg/ml), and median BNP for the hsPDA group was 561 pg/ml (IQ: 154-1036 pg/ml).
|Figure 2: Boxplot showing the median B-type natriuretic peptide levels with the interquartile ranges for infants who were diagnosed with either no patent ductus arteriosus, nonsignificant patent ductus arteriosus, or hemodynamically significant patent ductus arteriosus by echocardiogram. BNP - B-type natriuretic peptide; nsPDA - Nonsignificant patent ductus arteriosus; hsPDA - Hemodynamically significant patent ductus arteriosus|
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A ROC curve with data from all 95 preterm infants was created by combining the BNP levels, drawn at the time of the first echocardiogram, of the no PDA and nsPDA groups (hereafter referred to as the nsPDA group) and comparing these to the hsPDA group [Figure 3]. The area under the curve was 0.87. A cutoff BNP level of 276 pg/ml yielded a sensitivity of 70%, a specificity of 87%, and a likelihood ratio of 5.4 for detecting an hsPDA.
|Figure 3: Receiver operator characteristic curve describing the ability of B-type natriuretic peptide to predict a hemodynamically significant patent ductus arteriosus in preterm infants 24-31 6/7 weeks gestation. The area under the curve was 0.87. A cutoff B-type natriuretic peptide level of 276 pg/ml yielded a sensitivity of 70% and a specificity of 87% for detecting a hemodynamically significant patent ductus arteriosus|
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When we looked at whether BNP levels on DOL 1 could predict if an infant would have hsPDA on DOL 5, we found that there was no significant difference in BNP levels between the nsPDA group (median BNP level 111 pg/mL, IQ: 44-200 pg/mL) and hsPDA group (median BNP level 183 pg/mL, IQ: 32-389 pg/mL, P = 0.13).
B-type natriuretic peptide and gestational age
To evaluate whether BNP levels differed based on degree of prematurity, infants were divided into two gestational age groups, 24 0/7-27 6/7 weeks (hereafter known as the "extremely premature" infants) and 28 0/7-31 6/7 weeks (hereafter known as the "premature" infants). BNP levels done on DOL 1 in the nsPDA group (diagnosed by echocardiogram on DOL 5) were compared. The results revealed no significant difference between these two gestational age groups, median BNP level 115 pg/ml (IQ: 38-255 pg/ml) in the extremely premature group versus median BNP level of 110 pg/ml (IQ: 48-182 pg/ml) in the premature group. However, by DOL 5, there was a significant difference with the extremely premature infants having a higher median BNP level of 151 pg/ml (IQ: 26-469 pg/ml) versus the premature infants who had a lower median BNP level of 19 pg/ml [IQ: 7-47 pg/ml, P = 0.003, [Figure 4]. When looking at infants with hsPDA, they were again divided by gestational age into two groups as mentioned above. Median BNP levels on DOL 1 were significantly lower in the extremely premature infants who had median BNP level of 104 pg/ml (IQ: 19-294 pg/ml) versus the premature infants whose median BNP level was 358 pg/ml (IQ: 142-619 pg/ml, P = 0.03). This difference had disappeared by DOL 5; the median BNP level in the extremely premature infants was 609 pg/ml (IQ: 147-1223 pg/ml), and the median BNP level in the premature infants was 701 pg/ml [IQ: 102-2138 pg/ml, [Figure 5].
|Figure 4: Boxplot showing the median B-type natriuretic peptide levels with the interquartile ranges on day of life 1 (a) and day of life 5 (b) in infants diagnosed with a nonsignificant patent ductus arteriosus by echocardiogram. Infants were divided into two gestational age groups, "24-27" includes infants born at 24 0/7-27 6/7 weeks gestational age and "28-31" includes all infants born at 28 0/7-31 6/7 weeks gestational age. There was no significant difference between gestational age groups on day of life 1, P = 0.92, but there was a significant difference on day of life 5, *P = 0.003. BNP - B-type natriuretic peptide|
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|Figure 5: Boxplot showing the median B-type natriuretic peptide levels with the interquartile ranges on day of life 1 (a) and day of life 5 (b) in infants diagnosed with a hemodynamically significant patent ductus arteriosus by echocardiogram. Infants were divided into two gestational age groups, "24-27" includes infants born at 24 0/7-27 6/7 weeks gestational age and "28-31" includes all infants born at 28 0/7-31 6/7 weeks gestational age. A significant difference between gestational age groups was seen on day of life 1, *P = 0.03, but was not seen on day of life 5, P = 0.8. BNP - B-type natriuretic peptide|
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When looking at infants in the extremely premature group, BNP levels in the nsPDA group were not significantly different on DOL 1 compared to those infants with hsPDA (median BNP level, 115 pg/ml [IQ: 38-255 pg/ml] vs. 104 pg/ml [IQ: 19-294 pg/ml], respectively). However, by DOL 5, there was a statistically significant difference; median BNP level in the nsPDA group was 151 pg/ml (IQ: 26-469 pg/ml) versus 608.5 pg/ml (IQ: 147-1223 pg/ml) in infants with hsPDA [P = 0.02, [Figure 6]. Infants in the premature group had significant differences in BNP levels on both DOL 1 and DOL 5 in infants in the nsPDA group versus those infants in the hsPDA group; DOL 1 BNP levels were 110 pg/ml (IQ: 48-182 pg/ml) in nsPDA group versus 358 pg/ml (IQ: 142-619 pg/ml) in the hsPDA group (P = 0.002); DOL 5 BNP levels were 19 pg/ml (IQ: 7-47 pg/ml) in the nsPDA group versus 701 pg/ml (IQ: 102-2138 pg/ml) in the hsPDA group [P = 0.0006, [Figure 7].
|Figure 6: Boxplots showing the median B-type natriuretic peptide levels with the interquartile ranges on day of life 1 (a) and day of life 5 (b). Infants who were 24 0/7-27 6/7 weeks of gestation were divided into two groups based on the grade of patent ductus arteriosus determined by their first echocardiogram, no patent ductus arteriosus or nonsignificant patent ductus arteriosus, and hemodynamically significant patent ductus arteriosus. There was no statistical difference between the two groups on day of life 1, but there was statistically significant difference on day of life 5, *P = 0.03. BNP - B-type natriuretic peptide; nsPDA - Nonsignificant patent ductus arteriosus; hsPDA - Hemodynamically significant patent ductus arteriosus|
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|Figure 7: Boxplots showing the median B-type natriuretic peptide levels and interquartile ranges for infants who were 28 0/7-31 6/7 weeks gestation and had either no patent ductus arteriosus or nonsignificant patent ductus arteriosus and hemodynamically significant patent ductus arteriosus based on echocardiogram. (a) The median B-type natriuretic peptide level on day of life 1 was significantly different between the two groups, *P = 0.002. (b) The median B-type natriuretic peptide level on day of life 5 in the same infants was also statistically significantly different, *P = 0.0006. BNP - B-type natriuretic peptide; nsPDA - Nonsignificant patent ductus arteriosus; hsPDA - Hemodynamically significant patent ductus arteriosus|
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A ROC curve of BNP levels on DOL 5 in the extremely premature group gives an area under the curve of 0.71. When choosing a cutoff value of 276 pg/ml (the cutoff value obtained from the initial ROC curve using data from both gestational age groups), this yielded a 69% sensitivity, a 68% specificity, and a likelihood ratio of 2.2 for detecting hsPDA. A similar ROC curve was created using data from the premature group which gave an area under the curve of 0.89. Again, using the cutoff value of 276 pg/ml, this gave a 63% sensitivity, a 94% specificity, and a likelihood ratio of 9.4 for detecting hsPDA.
| Discussion|| |
To the best of our knowledge, this is the largest prospective study looking at BNP levels as a marker for predicting hsPDA in preterm neonates. Our results propose that a cutoff BNP level of 276 pg/ml was suggestive of hsPDA in a preterm infant of <32 weeks gestation when the level is drawn on DOL 5. The notion that elevated BNP levels are associated with increasing PDA size is not a novel concept, but the wide range of cutoff values published in the literature of what value signifies a hsPDA, from 7 to 1110 pg/ml, has prevented the usage of BNP as a reliable biomarker for the treatment and management of hsPDA., In our study, by excluding infants with congenital heart disease, infection, or pulmonary hypertension, we attempted to better define BNP produced solely in response to the ventricular wall stress as a result of hsPDA. However, even with a larger number of patients than in previous studies, there was still a wide range of BNP levels associated with each PDA group, suggesting that perhaps there might be other factors contributing to BNP production.
To evaluate the effect that the degree of prematurity had on BNP production, we stratified the infants into two gestational age groups. Our results suggest that the more immature the myocardium, the decreased ability, at least initially, to produce BNP in response to ventricular wall stress. BNP levels in the extremely premature infants were similar between those with and without hsPDA on DOL 1. However, by DOL 5, those infants with hsPDA had a significantly higher BNP level. Furthermore, when we compared the premature infants to the extremely premature infants who had hsPDA, we again saw this delayed elevation in BNP level in the extremely premature infants. Lee et al. suggested that BNP levels on the first DOL can be useful in predicting which infants will go on to develop a hsPDA. Our results show that this is the case for the premature infants, but not for the extremely premature infants.
The cutoff BNP level of 276 pg/ml that was determined from the ROC curve generated with the combined data from both gestational age groups may not be appropriate for every preterm infant as shown by the changes in sensitivities, specificities, and likelihood ratios when looking at the ROC curves based on gestational age. Using this cutoff value, you have 68% specificity for detecting hsPDA in the extremely preterm group versus a 94% specificity when using this same cutoff value in the preterm group. Given that preterm infants often have a difficult time maintaining hemodynamic homeostasis when transitioning to extrauterine life, especially extremely low birth weight infants, one can suppose that their ability to adapt postnatally may affect ventricular wall stress and subsequently the BNP level. Our data show the predictive ability of BNP to suggest hsPDA changes depending on the gestational age and, therefore, using one cutoff value for all preterm infants is not appropriate.
As noted previously, several other factors besides hsPDAs can cause elevations in BNP levels; diagnoses such as congenital heart disease, infection, and pulmonary hypertension can cause increased ventricular wall stress. Although we excluded infants with these diagnoses, one of the limitations of the present study is that we did not record the degree of respiratory distress the infant was experiencing which may have contributed to the variability in BNP levels that were recorded within each PDA grade. The effect of respiratory distress on BNP production was suggested in a study by da Graca et al. In addition, given the dynamic nature of the cardiovascular system in preterm infants, the DOL that the sample was drawn as well as the timing of the BNP sample in relation to the timing of the echocardiogram (although both were done on the same day) may have also contributed to this variability. Future studies with an even larger sample size and taking into account factors such as respiratory distress and hemodynamic status could help create even more precise cutoff values for BNP based on gestational age.
The usefulness of BNP levels in the neonatal population continues to be examined. The results contained herein add to the growing body of evidence that BNP levels can provide valuable information on the degree of stress the PDA is causing the myocardium. This study, with the largest number of infants to date, suggests that BNP levels on DOL 1 are not helpful in predicting whether a preterm infant will go on to develop hsPDA as suggested in previous studies. However, by DOL 5, BNP levels above 276 pg/ml showed good correlation with hsPDA, but there continued to be a wide range of values within the hsPDA group. Because of this variability and the effect that gestational age has on BNP production, we suggest that BNP levels may be more useful as a trending tool to monitor the ventricular stress caused by hsPDA. This additional information could help the clinician decide whether or not to administer treatment (or retreatment), and in equivocal cases, whether a repeat echocardiogram is indicated.
| Conclusion|| |
A cutoff BNP level of 276pg/ml on DOL 5 in preterm infants <32 weeks gestation is suggestive of a hsPDA. However, we also found that gestational age has a significant impact on the ability of the preterm infant to produce BNP in response to a hsPDA and, therefore, different cutoff values based on gestational age may be appropriate.
We wish to acknowledge all the families that participated in this study without whom this research would not be possible. We also wish to thank the Capital Region Pediatric Cardiology Group for performing the study echocardiograms on the infants and James Cummings, MD, for his help in reviewing this manuscript.
Financial support and sponsorship
This research was supported by the Department of Pediatrics at Albany Medical Center. The BNP cartridges and the point of care machine used to run the blood samples were donated by Alere, Inc.
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7]