Abstract
Objective:
Although B-type natriuretic peptide (BNP) concentrations appear to be useful for detecting the presence of a PDA, there is no information about their usefulness for monitoring changes in PDA shunt magnitude.
Design:
We performed a retrospective analysis of paired BNP - echocardiographic measurements (obtained from infants (24 – 32 weeks gestation) with clinical suspicion of PDA).
Results:
Individual BNP concentrations (n=146, from 88 infants) were significantly related to shunt magnitude at the time of the measurement and had good discriminating power for detecting a moderate-or-large shunt (area under receiver-operator characteristic curves (ROC-AUC)=0.85). 36 infants had serial BNP-echo pairs (n=91) measured during their hospitalization. Changes (either increases or decreases) in BNP concentrations over time had only fair discriminating power (ROC-AUC=0.76) for detecting increases or decreases, respectively, in shunt magnitude.
Conclusion:
The high degree of variability in the measurements made them less useful for monitoring changes in magnitude.
Keywords: patent ductus arteriosus, B-type natriuretic peptide, BNP, indomethacin, ductus ligation
Introduction
More than 30% of preterm infants born before 32 weeks of gestation have a patent ductus arteriosus (PDA) that fails to close after birth. In preterm infants, a PDA alters mesenteric blood flow, impairs pulmonary mechanics, increases the risk of pulmonary hemorrhage, and prolongs the need for mechanical ventilation (1–10). The echocardiogram has been used as a gold standard for determining the presence of a PDA and for evaluating temporal changes in the magnitude of a PDA left-to-right shunt. Unfortunately, frequent echocardiographic studies can destabilize an infant, may not be readily available in all institutions, and increase hospital costs.
B-type natriuretic peptide (BNP) is a vasoregulatory peptide that is synthesized mainly in the cardiac ventricles. BNP is released into the circulation in response to increases in cardiac volume, pressure loading and following ventricular stress (11). BNP concentrations have been shown to be an excellent screening tool for differentiating cardiac from non-cardiac causes of dyspnea in adults, with sensitivities and specificities that are reported to surpass those of clinical and radiologic methods. (12–15).
Numerous studies suggest that elevated BNP concentrations may be useful for detecting the presence of a PDA in premature neonates (16–22). Recently, several authors have suggested that by using BNP measurements to monitor changes in PDA shunt magnitude, the need for repeated echocardiography may be obviated. Although BNP concentrations decrease to levels comparable to those in preterm infants without a PDA following successful treatment and elimination of the left-to-right shunt (21, 23), no studies to date have reported on the ability of BNP measurements to detect worsening or increasing degrees of shunt magnitude.
Since 2004, BNP measurements have been used (in addition to clinical and echocardiographic examinations) to evaluate and monitor preterm patients with a PDA in the William H. Tooley Nursery at University of California San Francisco. We performed a retrospective analysis of paired BNP and echocardiographic measurements to determine how well BNP measurements reflect changes in PDA shunt magnitude. We hypothesized that changes in serial BNP concentrations would accurately reflect the changes in PDA shunt magnitude (determined by echocardiography) that occur over the same time period.
Methods:
Patient Population:
This project was approved by the Institutional Review Board of the University of California San Francisco. We performed a retrospective analysis to determine the accuracy of BNP measurements in 1) detecting and determining the magnitude of a PDA shunt, and 2) in monitoring changes (either increases or decreases) in PDA shunt magnitude. Between January 2004 and May 2008, 797 infants, with gestational ages between 24 and 32 weeks, were admitted to the nursery. Echocardiograms and BNP measurements were ordered by the attending neonatologist to evaluate a known or suspected PDA. Infants qualified for the study by having at least one BNP-echo pair (defined as a BNP concentration measured on the same day as an echocardiogram). Infants were excluded from the study if they were less than 5 days old at the time of the measurement or if they had congenital anomalies/congenital heart disease, pulmonary hypertension, hypotension requiring vasopressor support, documented sepsis, necrotizing enterocolitis, or serum creatinine >2.0 mg /dl since these conditions have been associated with increased BNP concentrations (16–18, 24–31).
The echocardiographic studies included two dimensional imaging, M-mode, color flow mapping and Doppler interrogation as previously described (32). Echocardiographic indices were obtained from standard subxiphoidal, precordial, apical, and suprasternal imaging windows utilizing standard imaging transducers (Sequoia ultrasound system, Siemens Medical Solutions, Mountain View, CA). Results were recorded for subsequent analysis. A single cardiologist (TT), blinded to clinical and BNP data, re-read all of the original echocardiograms. The ductus arteriosus was scored as either closed or open; if open, the left-to-right shunt was scored as small, moderate or large. The magnitude of the left to right shunt was scored subjectively by the cardiologist based on the presence of a combination of echocardiographic measures previously described as reflective of the degree of PDA shunt: ductus diameter ≥1.5 mm, left atrium-to-aortic root (LA/Ao) ratio ≥1.5, diastolic flow velocity in the left pulmonary artery >0.2 m/sec, and presence of holodiastolic reversal of flow in the descending aorta (at the level of the diaphragm) (16, 33–35).
Venous blood samples for BNP were sent to the Central Laboratory of the Hospital and assayed within 2 hours of collection using the Triage BNP assay (Biosite Diagnostics Inc., San Diego, California, USA). The assay detects BNP concentrations between 5 pg/ml to 5000 pg/ml. The average total imprecision of the assay (determined by testing control blood samples that had BNP added to concentrations throughout the range of the standard curve) was ≤12%. BNP concentrations in normal adults (without congestive heart failure) are reported to be ≤ 40 pg/ml in our Central Laboratory.
Statistics:
Statistical analysis was performed using Stata version 10 (Stata, College Park, TX, USA). Continuous variables with non-parametric distribution were compared using the Wilcoxon rank sum test; categorical variables were compared with the chi square test as well as univariate and multivariate logistic regression. Box and whisker plots were used to show the distribution of BNP levels. All hypotheses were two-tailed.
Our specific aims were to determine the accuracy of BNP measurements in 1) detecting and determining the magnitude of a PDA shunt, and 2) in monitoring changes (either increases or decreases) in PDA shunt magnitude.
For Specific Aim 1, the sensitivities, specificities, and likelihood ratios of various BNP concentrations were calculated for diagnosing either a “large” or a “moderate-or-large PDA” shunt. Receiver-operator characteristic (ROC) curves were constructed to determine the discriminating power of using BNP to detect moderate or large PDA shunts.
For Specific Aim 2 our primary clinical interest was to determine how well an INCREASE in BNP concentration over time could identify a PDA shunt that was worsening (i.e., increasing in shunt magnitude) during the same time period. We wanted to know how well an INCREASE in BNP concentration could differentiate a worsening PDA shunt from PDA shunts that were stable or improving. Sensitivities, specificities, likelihood ratios, and ROC curves were constructed to determine the discriminating power of various INCREASES in serial BNP concentrations to diagnose an INCREASE in shunt magnitude.
We also examined the ability of a DECREASE in BNP concentration over time to identify a PDA shunt that was getting better (i.e., decreasing in shunt magnitude during the same time period). Sensitivities, specificities, likelihood ratios, and ROC curves were constructed to determine the discriminating power of various DECREASES in serial BNP concentrations to differentiate a PDA shunt that was improving from PDA shunts that were stable or deteriorating.
Results:
Patient Demographics
88 infants qualified for the study and a total of 146 BNP-echo pairs were analyzed (Table 1). Based on the echocardiogram, the ductus arteriosus was subjectively scored as either closed (n=23) or open (n=123); if open, the left-to-right shunt was scored as small (n=47), moderate (n=28) or large (n=48). Table 1 shows the distribution of echocardiographic indicators (that reflect the magnitude of PDA shunt flow (16, 33–35)) among the different PDA shunt groups (closed, small, moderate or large shunts).
Table 1:
Infant and echocardiographic characteristics of study population
| Infant characteristics (N=88) | |
|---|---|
| Gestation (weeks) |
27.3 (2.1) |
| Birthweight (grams) |
980 (276) |
| Postnatal Age (days) |
13 (8.9) |
| Males (%) |
58 |
| Intrauterine Growth Restriction (%) |
7 |
| Intraventricular Hemorrhage Grade ≥ 3 (%) |
14 |
| Echocardiographic characteristics (N=146) | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| PDA Shunt | Ductus Diameter (mm) |
LA:Ao ratio |
LPA diastolic velocity (m/sec) | DAo flow reversal | ||||||||
| N (%) | Mean (SD) | % | Mean (SD) | % | Mean (SD) | % | % | |||||
| > 1.5 | <1.5 | > 1.5 | <1.5 | >0.2 | ≤0.2 | Yes | No | |||||
| Closed | 23 (16) | 0 (0) |
0 | 100 | 1 (0) |
0 | 100 | 0 (0) |
0 | 100 | 0 | 100 |
| Small | 47 (32) | 1.2 (0.43) |
33 | 67 | 1.3 (0.29) | 26 | 74 | 0.13 (0.24) | 12 | 88 | 8 | 92 |
| Moderate | 28 (19) | 1.8 (0.32) |
86 | 14 | 1.6 (0.29) | 56 | 44 | 0.23 (0.08) | 53 | 47 | 60 | 40 |
| Large | 48 (33) | 2.3 (0.49) |
98 | 2 | 1.8 (0.49) | 74 | 26 | 0.32 (0.13) | 93 | 7 | 95 | 5 |
Values = mean (SD); LA:Ao ratio = Left atrium:Aortic root ratio; LPA diastolic velocity = Left pulmonary artery diastolic velocity; DAo flow reversal = Holodiastolic flow reversal in the Descending Aorta
Accuracy of BNP in diagnosing a large or a moderate-or-large PDA shunt:
48% of the paired BNP-echo measurements were made in the presence of a closed or small PDA; 52% were made in the presence of a moderate or large PDA shunt (Table 1). BNP concentrations were significantly related to the magnitude of the PDA shunt (Figure 1). For any shunt magnitude, the BNP concentrations were significantly greater than those of smaller shunts and significantly less than those of larger shunts. In logistic regression analyses, BNP concentrations were significantly associated with the presence of either “large” or “moderate-or-large” PDA shunts. The association was independent of other variables (gestation, birthweight, gender, and postnatal age at the time of the measurement) (adjusted OR for “moderate to large” PDA shunt with every 100 pg/ml increase in BNP = 2.81, 95% confidence interval 1.79–4.40, p<0.001; for “large” PDA shunt with every 100 pg/ml increase in BNP adjusted OR =1.44 (95% confidence interval: 1.23–1.68), p=0.000).
Figure 1: The relationship between BNP concentrations and PDA shunt magnitude.
Data are presented as box and whisker plots. The horizontal line is the median value; the top and bottom of the box represent the 75th and 25th percentiles, respectively; and the whiskers represent the 10th and 90th percentiles. The values over the whiskers are the median and range.
Table 2 depicts the sensitivities, specificities, and likelihood ratios of various BNP concentrations in diagnosing either a “large” or a “moderate-or-large PDA” shunt. We used ROC analysis to determine the discriminating power of using BNP to detect moderate or large PDA shunts. In general, one expects that the area under a ROC curve should be greater than 0.90 for a test to be considered excellent in its ability to discriminate one condition from another; tests with areas between 0.90 and 0.80 are considered good; tests with areas below 0.80 are considered to have fair discriminating ability, and those with areas below 0.70 are considered to be poor. The area under the ROC curve for the detection of a “moderate-or-large” PDA was 0.85, and for the detection of a “large” PDA was 0.84.
Table 2:
Relationship between BNP cutoff values and hemodynamically significant PDA shunts
| BNP > (pg/mL) |
Sensitivity (%) |
Specificity (%) |
Likelihood Ratio (+) | Likelihood Ratio (−) |
|---|---|---|---|---|
| Predicting Moderate-or-Large PDA shunt: | ||||
| 40 | 92 | 46 | 1.70 | 0.17 |
| 60 | 87 | 57 | 2.03 | 0.23 |
| 80 | 82 | 66 | 2.38 | 0.28 |
| 100 | 76 | 70 | 2.54 | 0.34 |
| 200 | 59 | 91 | 6.91 | 0.45 |
| 300 | 45 | 94 | 7.82 | 0.59 |
| Predicting Large PDA shunt: | ||||
| 40 | 98 | 38 | 1.57 | 0.06 |
| 60 | 92 | 47 | 1.73 | 0.18 |
| 80 | 88 | 55 | 1.95 | 0.23 |
| 100 | 83 | 60 | 2.09 | 0.28 |
| 200 | 69 | 82 | 3.74 | 0.38 |
| 300 | 54 | 88 | 4.42 | 0.52 |
N= 146 BNP-echo pairs (from 88 infants). Likelihood ratios are reflective of the inherent ability of a test to increase or decrease the likelihood of a condition. An LR+ of >1 means that a positive test result will increase the patient’s probability of having a moderate-or-large PDA shunt. An LR- of <1 means that a negative test result will decrease the patient’s probability of having a moderate-or-large PDA shunt. In general, an LR+ of >10, or an LR – of <0.1 indicate that the test has an excellent chance of identifying the correct condition. LR’s of 5–10 or 0.1–0.2 only have a good chance of identifying the correct condition.
Accuracy of BNP changes as a reflection of changes in PDA shunt magnitude:
In order to determine if changes in BNP measurements over time accurately reflect changes in PDA shunt magnitude, we examined serial BNP-echo pairs in infants that had more than 1 BNP-echo pair measured during their hospitalization. 91 serial BNP-echo pairs were examined in 36 infants.
Our primary clinical interest was to determine how well an INCREASE in BNP concentration over time could identify a PDA shunt that was worsening (i.e., increasing in shunt magnitude) during the same time period. We wanted to know how well an INCREASE in BNP concentration could differentiate a worsening PDA shunt from PDA shunts that were stable or improving. We also wanted to examine the ability of a DECREASE in BNP concentration over time to identify a PDA shunt that was getting better (i.e., decreasing in shunt magnitude during the same time period).
A PDA shunt was considered to have INCREASED in size if the shunt magnitude increased from a) a closed ductus lumen to a small, moderate or large shunt, b) a small shunt to a moderate or large shunt, or c) a moderate shunt to a large shunt. Changes in the opposite direction were used to define a DECREASE in shunt size. Changes in BNP concentration were expressed as the percent change from the initial BNP measurement. Since the imprecision of the BNP assay is ≤ 12%, we considered any increase or decrease in BNP concentration of less than 15% to be no change.
Figure 2 shows the relationship between a change in PDA shunt magnitude (either an increase, a decrease, or no change) and the change in BNP concentration during the same interval. The change in BNP concentration (between the first and second measurement) was significantly higher when the PDA shunt increased in magnitude, than when it was either unchanged or decreased in magnitude. Conversely, the change in BNP concentration was significantly lower when the shunt decreased in size, than when it was either unchanged or increased in size (Figure 2).
Figure 2: The relationship between changes in BNP concentrations and changes in PDA shunt magnitude.
Data are presented as box and whisker plots. See Figure 1 legend for explanations.
In logistic regression analyses, increases in BNP concentration were significantly associated with increases in PDA shunt magnitude, and decreases in BNP concentration were significantly associated with decreases in PDA shunt magnitude. These associations were independent of other variables (gestation, birthweight, gender, and postnatal age at the time of the measurement) (adjusted OR for an increase in PDA shunt magnitude with an increase in BNP concentration was 9.63, 95% confidence interval 2.87 to 32.35, p<0.001; adjusted OR for a decrease in PDA shunt magnitude with a decrease in BNP concentration was 4.93, 95% CI 1.44 to 16.88, p=0.01).
We generated ROC curves to determine the clinical utility of using changes in BNP concentration to predict changes in PDA shunt magnitude. Using increases in BNP concentration to predict increases in PDA shunt magnitude, the area under the ROC curve was 0.76. Using decreases in BNP concentration to predict decreases in PDA shunt magnitude, the area under the ROC curve was 0.78. Table 3 lists sensitivities, specificities and likelihood ratios for various changes in BNP concentrations.
Table 3:
Relationship between increases and decreases in serial BNP concentrations and increases and decreases in PDA shunt magnitude
| Predicting an INCREASE in PDA shunt magnitude: | ||||
|---|---|---|---|---|
| BNP INCREASED by ≥ | Sensitivity (%) |
Specificity (%) |
Likelihood Ratio (+) | Likelihood Ratio (−) |
| 15% | 59 | 75 | 2.40 | 0.55 |
| 30% | 59 | 79 | 2.79 | 0.52 |
| 50% | 59 | 79 | 2.79 | 0.52 |
| 100% | 47 | 84 | 2.98 | 0.63 |
| 200% | 35 | 88 | 2.87 | 0.74 |
| 300% | 29 | 91 | 3.35 | 0.78 |
| Predicting a DECREASE in PDA shunt magnitude: | ||||
| BNP DECREASED by ≥ | Sensitivity (%) |
Specificity (%) |
Likelihood Ratio (+) | Likelihood Ratio (−) |
| 15% | 82 | 54 | 1.76 | 0.34 |
| 30% | 82 | 57 | 1.88 | 0.32 |
| 50% | 73 | 64 | 2.01 | 0.43 |
| 75% | 55 | 86 | 3.76 | 0.53 |
| 95% | 9 | 100 | n/a | 0.91 |
N= 91 BNP-echo pairs (from 36 infants). see Legend for Table 2 for explanations of Likelihood Ratios.
The comparisons between increases in serial BNP concentrations and increases in PDA shunt magnitude were made by comparing the binary variable increase in BNP (increase in BNP versus decrease or no change in BNP) with the Binary variable increase in PDA shunt (increase in shunt versus decrease or no change in shunt).
Similarly, the comparisons between decreases in serial BNP concentrations and decreases in PDA shunt magnitude were made by comparing the binary variable decrease in BNP (decrease in BNP versus increase or no change in BNP) with the Binary variable decrease in PDA shunt (decrease in shunt versus increase or no change in shunt).
Using the absolute change in BNP concentration as our discriminating test (rather than the percent change in BNP concentration) did not alter our findings (data not shown).
Discussion:
Our results are consistent with prior studies that found that BNP concentrations are significantly related to the magnitude of a PDA shunt (Figure 1) (16–22). However, despite this significant association, BNP concentrations appear to have, at best, only a good ability to discriminate between moderate-to-large shunts and those that are small-or-closed. We should point out that, although a single BNP value is not an excellent test for determining PDA shunt magnitude, having a BNP concentration ≤40 pg/mL indicates that there is an extremely low likelihood that a large left-to-right PDA shunt is present.
Other investigators have observed a decrease in BNP concentrations following pharmacologic or surgical PDA closure (19, 21, 23) and have suggested that serial BNP measurements may be used to monitor changes in PDA shunt magnitude. Since none of the previous studies reported about either the ability of BNP measurements to detect spontaneously closing PDAs or PDAs that were developing worsening shunts (increasing degrees of shunt magnitude), we examined the accuracy of using serial measurements of BNP to monitor changes in PDA shunt magnitude. We were particularly interested in the ability of serial BNP measurements to discriminate between PDA shunts that were progressively getting larger and those that were stable or decreasing in magnitude. Since the imprecision of the BNP assay is <12%, we assumed that a change in BNP concentration ≥ 15% would be the most sensitive discriminator for identifying a change in PDA shunt magnitude. We found that any decrease in BNP concentration of ≥ 15% only detects 82% of the PDA shunts that decreased in magnitude during the same interval (Table 3). Increases in BNP concentration were even less sensitive in their ability to detect increases in shunt magnitude; any increase in BNP concentration of ≥ 15% only detected 59% of PDA shunts that increased in magnitude during the same interval. The areas under the ROC curves reveal that both increases and decreases in BNP concentrations should be considered only fair indications that there have been concurrent increases and decreases in shunt magnitude, respectively.
Plasma BNP has a half-life of 20 minutes (36). In our study the echocardiogram and whole blood BNP measurements were performed at different times and therefore may not have reflected the same hemodynamic state. However, the evaluations were performed on the same day that the neonatologists were concerned that a symptomatic PDA might be present. The difference in times between the tests reflects the normal delays that occur in common clinical practice in a busy intensive care environment. It is unlikely that the difference between the measurements is due to rapid fluctuations in steady state hemodynamics. We observed 2 infants where the BNP concentrations steadily declined over 3 weekly measurements at the same time that the echocardiographic measurements of PDA shunt size changed in the opposite direction (from moderate to very large - with ventricular dilitation and mitral regurgitation). This asynchrony (between changes in BNP and echocardiographic shunt measurements) has been observed by others (21). Why some neonates have low BNP concentrations despite a large hemodynamically significant shunt is still unclear (19, 37).
Recently, the N-terminal byproduct of BNP formation, N-terminal proBNP, has been used to detect the presence of a PDA (11). Future studies will be needed to evaluate the usefulness N-terminal proBNP measurements for predicting changes in PDA shunt magnitude.
In conclusion, we found that although BNP concentrations were significantly related to PDA shunt magnitude, the high degree of variability in the measurements made them less useful for monitoring changes in magnitude. The ROC curves reveal that increases and decreases in BNP concentration have only fair predictive ability in determining the direction of change in shunt magnitude.
Acknowledgements:
This study was supported in part by grants from the U.S. Public Health Service, NHLBI (HL46691), NIH/NCRR UCSF-CTSI (UL1 RR024131) and a gift from the Jamie and Bobby Gates Foundation.
Abbreviations:
- PDA
Patent ductus arteriosus
- BNP
B-type natriuretic peptide
- ROC
Receiver operator characteristics
- AUC
Area under the curve
Footnotes
Conflict of Interest:
None of the authors have any financial agreement with any company whose product figures prominently in the manuscript.
Conflict of interests: We have no conflict of interests.
Disclosures: None.
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