Published online June 1, 2006
PEDIATRICS Vol. 117 No. 6 June 2006, pp. 2183-2189 (doi:10.1542/peds.2005-1387)
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Longitudinal Changes of Brain-Type Natriuretic Peptide in Preterm Neonates

Ralph L. da Graca, MDa,b, Denise C. Hassinger, MDa,b, Patrick A. Flynn, MDa,c, Cristina P. Sison, PhDd, Mirjana Nesin, MDa,b and Peter A.M. Auld, MDa,b

a Department of Pediatrics, New York Presbyterian Hospital, Weill Medical College of Cornell University, New York, New York
b Division of Newborn Medicine, New York Presbyterian Hospital, Weill Medical College of Cornell University, New York, New York
c Division of Pediatric Cardiology, New York Presbyterian Hospital, Weill Medical College of Cornell University, New York, New York
d Department of Statistics, North Shore-Long Island Jewish Health System, Manhasset, New York


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
OBJECTIVE. To determine age-related concentrations of brain-type natriuretic peptide in preterm infants using bedside Triage brain-type natriuretic peptide test and correlate it to the presence or absence of the patent ductus arteriosus and ventilatory support.

METHODS. Serum brain-type natriuretic peptide levels were measured in infants who were born at <32 weeks’ gestation from birth to 2 months of age. Serial echocardiograms were performed, until closure of the patent ductus arteriosus, or until discharge. Brain-type natriuretic peptide levels were correlated to the day of life, gestational age, presence or absence of the patent ductus arteriosus, and the degree of ventilatory support. Nineteen preterm infants (gestational age: 24–31 weeks; birth weight: 645–1670 g) were enrolled prospectively during the first 2 weeks of life. Serum brain-type natriuretic peptide levels (pg/mL) were determined in 177 blood samples, and 87 paired echocardiograms were performed.

RESULTS. Significant negative correlation was found between brain-type natriuretic peptide levels and the day of life and remained significant when the patients were stratified by gestational age (≤28 weeks and >28 weeks). Higher brain-type natriuretic peptide levels correlated with increasing grade of the patent ductus arteriosus. Significant differences in brain-type natriuretic peptide levels were seen with increasing ventilatory support. Comparisons between the size of patent ductus arteriosus and the degree of ventilatory support to brain-type natriuretic peptide levels revealed that the size of the patent ductus arteriosus was the major determinant of both brain-type natriuretic peptide levels and the degree of ventilatory support.

CONCLUSIONS. Similar to term infants, brain-type natriuretic peptide levels of preterm infants are related to the chronological age and decline during the first month of life. Rapid bedside Triage brain-type natriuretic peptide is a potentially valuable and practical assay in determining the hemodynamic changes in preterm infants.

Key Words: B-type natriuretic peptide • Triage BNP • prematurity • preterm infants • patent ductus arteriosus

Abbreviations: BNP—brain-type natriuretic peptide • N-BNP—N-terminal BNP • CHF—congestive heart failure • PDA—patent ductus arteriosus • GA—gestational age • NCPAP—nasal continuous positive airway pressure • IQR—interquartile range • DOL—day of life • RDS—respiratory distress syndrome

Brain natriuretic peptide (BNP) is 1 of the cardiac natriuretic peptides that are responsible for the regulation of physiologic vascular changes in response to pressure or fluid overload. Originally described in extracts of porcine brain,1 it is present in the human brain but secreted mainly by ventricular myocytes in response to stretching. BNP contains 108 amino acid residues that release an active 32–amino acid molecule and an inactive N-terminal fragment. This hormone and other cardiac peptides induce vasodilation, natriuresis, and diuresis and acts to antagonize the effects of the renin-angiotensin-aldosterone system.1,2

In adults, both BNP and N-terminal BNP (N-BNP) are highly sensitive and specific diagnostic and prognostic markers for the evaluation and treatment of congestive heart failure (CHF). It also has been used to evaluate acute dyspnea, left ventricular end-diastolic dysfunction, pulmonary hypertension, and myocardial infarction and even predict sudden cardiac death in patients with CHF.3–6 Normal values of plasma N-BNP and N-terminal atrial natriuretic peptide have been reported in healthy individuals from the perinatal period to adulthood.7–9 Reports also have discussed the use of N-BNP in correlation with the patent ductus arteriosus (PDA), in relation to therapy (nonsteroidal anti-inflammatory medications and surgery), and in CHF in children with congenital heart disease.10–12

Recently, a new blood test, Triage BNP (Biosite Diagnostics, San Diego, CA), has been approved by the Food and Drug Administration for bedside diagnosis of CHF in adults. This test can be performed on as little as 250 µL of whole blood and measures the active form of BNP within 15 minutes. To our knowledge, the usefulness and the normal values of BNP levels that are determined by Triage BNP have not been established in preterm neonates. The objective of this study was to determine physiologic changes of BNP in premature neonates, using bedside Triage BNP, from birth to 2 months of age and assess its relationship to the PDA and ventilatory support. The premature infant has a likelihood of cardiopulmonary and vascular morbidity that is specific to this patient population; therefore, it is difficult to obtain true normative data. Bedside Triage BNP is a potential clinical tool in the treatment of premature infants with PDA and respiratory distress. Ultimately, BNP levels may help clinicians to follow progression of disease and aid in the clinical decision-making of when closure of the PDA is necessary.


   METHODS
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 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
This was a prospective observational longitudinal study. The study was approved by Institutional Review Board of the Weill Medical College of Cornell University. Written parental consent was obtained before study enrollment. All infants who were <32 weeks’ gestational age (GA) and admitted directly or transferred to the NICU at New York Presbyterian Hospital of the Weill Cornell Medical Center were eligible for enrollment. Because infants who are <32 weeks’ GA frequently have more clinical implications for PDA therapy, near-term and infants who were 32 to 34 weeks’ GA were excluded. Infants with any genetic disorder, congenital anomalies, or congenital heart disease other than PDA also were excluded from the study. Limitations to enrollment included ability to obtain consent, precondition of a single investigator performing collection, correct calibration of Triage BNP device, and availability of the echocardiographer. Blood samples were collected in correlation to other blood draws to avoid excessive blood draws specifically for study purposes. BNP measurements were performed on day of enrollment and 3 times a week during the first 2 months of life. An echocardiogram was performed on the day of enrollment and every 4 to 5 days until documented closure of the PDA was noted or the patient was discharged. BNP measurements were paired with echocardiograms and performed within 1 hour of each other. Echocardiography was performed by a single cardiologist throughout the duration of the study.

Although subjective, PDA grade was used to standardize each echocardiogram evaluation during the course of the study. A PDA grade (left atrial to aorta ratio, ductal diameter, and diastolic flow in the descending aorta) was determined for each evaluation to assess the severity of PDA: 0, closed; 1, small; 2, moderate; 3, large.13,14 For assessment of the correlation with the severity of respiratory distress at the time of BNP determinations, the following ventilatory rating scale was used for the purpose of this study: 0, room air; 1, nasal cannula or nasal continuous positive airway pressure (NCPAP) with or without oxygen; 2, conventional ventilation requiring ≤30% fraction of inspired oxygen; 3, conventional ventilation/high-frequency oscillatory ventilation requiring >30% fraction of inspired oxygen). Assigning a ventilatory rating score allowed us to determine indirectly whether BNP and/or the grade of PDA correlated with the degree of respiratory distress. The plan of care for each patient was determined by the attending neonatologist, and BNP values were not available to the cardiologist and the clinical team.

Measurement of Plasma BNP
Plasma BNP levels were determined using the Triage BNP assay. Blood was collected in microtainers that contained potassium EDTA, and the assays were performed directly at the bedside. After addition of 250 µL of whole blood to the sample port of the test device, the blood cells were separated from the plasma by a filter. In the Triage BNP assay, plasma enters a reaction chamber that contains murine polyclonal fluorescence–tagged BNP antibodies. The reaction mixture was incubated for 2 minutes. 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 assay required ~15 minutes.

Because hemolysis can affect BNP values, the BNP levels from whole blood that was obtained by venipuncture and from the catheter were compared in patients who had an indwelling vascular catheter. The measured difference was within 5%. Most samples were obtained by venipuncture.

Statistical Analysis
Analysis of variance was conducted to compare BNP levels over time across various groups, such as gender (male versus female), race, GA, ventilatory rating, and PDA size. Bonferroni-like adjustments were applied for pairwise comparisons on finding significant group differences.

It was determined that a natural log transformation of the data conformed to the standard analysis of variance assumptions. Accordingly, all analyses were conducted using the log-transformed data but were reported in their original untransformed units to facilitate interpretation. For descriptive purposes, Spearman correlations were calculated to describe overall correlation between BNP and day of life. The {chi}2 test was used to determine association between categorical variables. These analyses were conducted under the weak (statistical) assumption of independence of daily measurements. The analysis of covariance method (Bland and Altman) was applied to determine correlations within patients.15

Sample Size Considerations
The sample size for this study was based on feasibility and not on any formal statistical power calculations. The number of patients in this study was limited to the available data collected during the specified study period and by difficulties in enrolling premature infants in a no-benefit research study.


   RESULTS
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 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Demographics
From June 2003 to March 2004, 19 premature infants were enrolled prospectively in the study. The demographics of the study infants are shown in Table 1. There were no significant differences when comparing birth weights and GA with gender and race. All infants were enrolled during the first 2 weeks of life: 16 on day of life (DOL) 0 to 2, 1 on DOL 4, and 2 on DOL 13. Infants were followed until 2 months of age or until discharge. On average, infants were followed for 25.5 days (median: 20 days; range: 8–72 days). Serum BNP levels were determined in 177 samples. Eighty-seven paired echocardiograms were performed from enrollment until documented closure of the PDA. Because in most infants the PDA closed before 2 months of age, more BNP levels than echocardiograms were obtained. The median number of BNP measurements was 8 per infant (range: 4–22). The median number of echocardiograms was 3 per infant (range: 1–10). Infants with large PDA had more echocardiograms performed and BNP measurements than infants with early PDA closure. Four patients received a trial of indomethacin: 3 for asymptomatic and 1 for symptomatic PDA. One asymptomatic PDA failed to close, and the patient with symptomatic PDA ultimately required surgery.


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  		TABLE 1 Demographics and Clinical Characteristics of Preterm Infants

 
During the course of the study, 12 of the 19 infants received surfactant therapy, 11 of the 12 infants were intubated and on ventilatory support at the time of enrollment, and 2 infants required high-frequency ventilation. The remaining 8 infants required either NCPAP or cannula with oxygen at the time of enrollment; only 1 of the 8 who received surfactant was placed onto NCPAP. Respiratory support that was required at the time of the testing was recorded and compared with serum BNP levels and the results of echocardiogram. Among the 19 enrolled infants, 7 had sepsis confirmed by a positive blood culture, 1 had meningitis, and 2 developed necrotizing enterocolitis. All enrolled patients survived their NICU course.

Correlation Between BNP and Postnatal Age
Figure 1 illustrates the distribution of logarithmic values of BNP during the first 2 months of life. The actual BNP levels (pg/mL) according to DOL are expressed as median with interquartile range (IQR; 25%–75%): DOL 0 to 1, 362 (94–780); DOL 2 to 3, 196 (115–1146); DOL 4 to 5, 159 (25–1060); DOL 6 to 7, 70 (23–227); DOL 8 to 10, 81 (17–289); DOL 11 to 14, 64 (24–191); DOL 15 to 30, 43 (12–158); DOL >30, 16 (6–48). BNP levels during the first few DOL were higher and declined exponentially over time. A significant negative correlation was seen between BNP and DOL (r = –0.34; P = .001). Correlations remained significant when infants were stratified according to GA (r = –0.34 [P = .0001] for ≤28 weeks and r = –0.47 [P = .0015] for >28 weeks. No significant difference was found when the 2 GA groups were compared with each other.


Figure 1
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  		FIGURE 1 Exponential changes of logarithmic BNP levels (pg/mL) in preterm neonates over time (n = 177 observations). Values are expressed as median with IQR (25%–75%).

 
Correlation Between BNP and Grade of PDA
BNP levels were paired to echocardiogram results and correlated to the grade of PDA (0, 1, 2, and 3). Eighty-seven paired samples were obtained during the study. The following BNP levels (pg/mL) were obtained for each PDA grade (median [IQR (25%–75%)]: grade 0, 31 (12–52); grade 1, 88 (27–285); grade 2, 145 (30–498); and grade 3, 833 (470–1060). Figure 2 depicts the distribution of logarithmic values of BNP levels according to the PDA grade. Significant differences in BNP levels were seen with increasing grade of PDA (P < .0001). In pairwise comparisons, significant differences were seen between PDA grades: 0 and 1, P < .014; 0 and 2, P < .001; 0 and 3, P < .001; 1 and 3, P < .001; and 2 and 3, P < .001.


Figure 2
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  		FIGURE 2 Logarithmic BNP levels (pg/mL) according to the grade of PDA: 0, closed; 1, small; 2, moderate; 3, large (n = 87 paired observations of echocardiogram at the time of BNP determination). Values are expressed as median with IQR (25%–75%).

 
Correlation Between BNP and Ventilatory Support
The following BNP levels (pg/mL) were obtained for different ventilatory ratings (median [IQR (25%–75%)]: rating 0, 9 (5–18); rating 1, 27 (12–75); rating 2, 176 (65–470); and rating 3, 256 (132–573). Figure 3 illustrates the distribution of logarithmic BNP values according to the degree of ventilatory support. Significant increases in the BNP levels were seen across increased degree of ventilatory support (P < .0001). In pairwise comparisons, significant differences were detected between ventilatory ratings: 0 and 1, P < .001; 0 and 2, P < .001; 0 and 3, P < .001; 1 and 2, P < .001; and 1 and 3, P < .001). No difference was seen between 2 and 3 (P = .720). Therefore, intubated patients represent a similar group in relation to their BNP values, and in additional subanalysis, we combined their measurements.


Figure 3
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  		FIGURE 3 Logarithmic BNP levels (pg/mL) according to the ventilatory rating: 0, room air; 1, nasal cannula or NCPAP with or without oxygen; 2, conventional ventilation requiring ≤30% fraction of inspired oxygen; 3, conventional ventilation/high-frequency oscillatory ventilation requiring >30% fraction of inspired oxygen (n = 177 paired observations of ventilatory rating score at time of BNP determination). Values are expressed as median with IQR (25%–75%).

 
Correlation of BNP, Grade of PDA, and Degree of Ventilatory Support
To determine whether there are significant correlations among BNP levels, PDA, and ventilatory support, we divided 87 sets of observations into 2 ventilatory groups: nonintubated (ventilatory ratings 0 and 1) and intubated (ventilatory ratings 2 and 3) and compared them with the size of the PDA: high-grade PDA (grade 3) and lower grade PDA (grades 0, 1, and 2). When grade 3 PDA was diagnosed by echocardiogram, 14 (82%) of 17 observations noted that these infants tended to be intubated (ventilatory ratings 2 and 3), in contrast to 29 (41%) of 70 observations of patients with lower grades of PDA (0, 1, and 2) that required intubation (P = .003).

Table 2 illustrates the relationship of logarithmic values of BNP levels, grade of PDA, and ventilatory rating to each other. BNP values are expressed as mean ± SEM and median (25%–75% IQR). Significant correlation was seen when comparing increasing size of the PDA with the degree of ventilatory support. Within lower PDA grades, BNP levels were significantly higher in the intubated than in the nonintubated infants. However, regardless of ventilatory support, no significant difference was seen in patients with high-grade PDA (grade 3). The overall patterns of change in BNP levels between PDA groups depended on the degree of ventilatory support (P < .02)


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  		TABLE 2 Correlations of BNP, Grade of PDA, and Ventilatory Rating

 

   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Rapid diagnostic tests are becoming a point of care in neonatal and adult medicine. Before such a test can be introduced into clinical practice, it is important to establish normative values and identify patient populations that may benefit from a test. In this study, we used bedside Triage BNP to measure postnatal changes of BNP levels in premature infants. Our results are similar to other published literature using N-terminal atrial natriuretic peptide and N-BNP tests that require larger blood volumes and the results of which are not available immediately.7–9

We have demonstrated after an initial increase on DOL 1 and 2 (that most likely represents perinatal vascular adaptation from fetal to neonatal circulation), BNP levels in premature infants declined exponentially during the first 2 months of life and reached similar values that have been reported in healthy adults and children (Fig 1).7,8 In contrast to healthy term infants, daily BNP levels in premature infants show greater variability over time.9 The difficulty in correlating BNP to the size of the PDA during the perinatal transition more likely correlates with changes in pulmonary arterial pressure and adaptation to normal circulation.16 However, the greater variability of BNP levels over time likely is related to cardiopulmonary morbidities (delayed closure of PDA, respiratory distress syndrome [RDS], fluid overload, etc) that are associated with prematurity. Our results showed no difference when patients were stratified by GA and indicate that comorbidities may be more relevant for the varying changes in the BNP levels than GA. In addition to the cardiopulmonary factors, other circulatory changes (septic shock) may affect BNP levels. Data from animal studies17 and adult literature18 indicate that cytokines (especially IL-6) may play a role in the upregulation of natriuretic peptides in ventricular myocytes and the release of prostaglandins in circulation that may relate to ductal opening. Because a significant number (37%) of premature infants in our study were exposed to chorioamnionitis or developed infections, the role of cytokines in the regulation of BNP production may be relevant for the clinical course in premature infants and their ability to undergo postnatal vascular adaptation.

Our results confirm already reported findings that the magnitude of PDA is the major determinant of elevated BNP.10,11 Infants who developed a large PDA (grade 3) have significantly higher levels of BNP than infants without PDA or with small- or moderate-sized PDA (Fig 2). Infants with moderate (grade 2) PDA may represent a nonhomogeneous group, as indicated by the wide SD of BNP levels (Fig 2). Some patients in this group had high BNP levels, indicating hemodynamically significant PDA, whereas the others with the same grade of PDA had lower levels of BNP and likely hemodynamically insignificant PDA. Alternatively, elevated BNP levels in an infant with small- or moderate-sized PDA may have other reasons for elevated BNP level: cardiac abnormalities (eg, myocarditis, ventricular dysfunction) or vascular cause other than postnatal circulatory adaptation (eg, persistent pulmonary hypertension of the newborn, fluid overload, transfusion).19,20

A positive correlation was established between ventilatory support and BNP levels (Fig 3). The likely explanation for these findings was the presence of a hemodynamically significant PDA. The increased degree of left-to-right shunting, pulmonary congestion with decreased lung compliance, and eventual progression to CHF have been described in RDS.21,22 Our study confirms these findings: infants with the highest grade of PDA (grade 3) had both higher BNP levels and a higher degree of ventilatory support (Table 2). It is likely that this group of infants would benefit from therapeutic intervention (eg, closure of PDA, fluid restriction).

Table 2 further describes infants with lower grades of PDA that required higher ventilatory support (intubated). These infants more likely had lung disease and therefore showed relatively lower BNP values. As described earlier, this likely is a nonhomogeneous group, and selected infants within this group may have evidence for elevated BNP levels other than the PDA. A significant difference between this group and infants who were not intubated and had low PDA grade suggests that significant respiratory disease may be secondary to a delayed decline in the pulmonary vascular resistance.16

Despite a small sample size and the various comorbidities that are associated with prematurity, we were able to establish a range of BNP values in premature infants during the first 2 months of life using a bedside device with immediate availability of results. Our study showed that the natural progression of circulatory changes over time was not related to GA but rather to comorbidities that premature infants experience during this period.10,11,16,19–22 Even in an extremely premature infant, BNP levels declined after the first few DOLs when the PDA was closed and RDS was not severe. BNP levels correlated best with the size of the PDA. Infants who have a large PDA and require a high degree of ventilatory support tend to have higher BNP levels and may represent a target group that would benefit from closure of the PDA.23 The importance of the utilization of BNP has not been shown to be diagnostic in this population. It is important to do additional studies and possibly multicenter trials to establish true normative ranges in premature infants, especially in the case in which BNP levels may serve as an indicator for earlier intervention (surgical ligation or medical therapy). However, it is important to emphasize that BNP levels should be used as an adjunct to clinical assessment and echocardiography and cannot be used independently in medical decision-making. In addition, Triage BNP may serve as a quick, reliable, and inexpensive tool to follow progression of cardiopulmonary and vascular disease and help to determine when echocardiography is required in such critically ill infants.


   FOOTNOTES
 
Accepted Dec 27, 2005.

Address correspondence to Ralph L. da Graca, MD, UMDNJ-New Jersey Medical School, Department of Anesthesiology, 185 S Orange Ave, MSB E-538, Newark, NJ 07103. E-mail: rdagraca{at}hotmail.com

The authors have indicated they have no financial relationships relevant to this article to disclose.


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 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
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PEDIATRICS (ISSN 1098-4275). ©2006 by the American Academy of Pediatrics




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