Diagnosing Signiﬁcant PDA Using Natriuretic Peptides in ... · blood assay for brain natriuretic peptide (BNP) or amino-terminal pro-B-type natriuretic peptide (NT-proBNP) may be

Diagnosing Significant PDA UsingNatriuretic Peptides in PretermNeonates: A Systematic ReviewMadhulika Kulkarni, MDa, Ganga Gokulakrishnan, MDa, Jack Price, MDb, Caraciolo J. Fernandes, MDa, Mariska Leeflang, PhDc,Mohan Pammi, MD, PhDa

abstract BACKGROUND AND OBJECTIVES: Echocardiogram is the gold standard for the diagnosis ofhemodynamically significant patent ductus arteriosus (hsPDA) in preterm neonates. A simpleblood assay for brain natriuretic peptide (BNP) or amino-terminal pro-B-type natriureticpeptide (NT-proBNP) may be useful in the diagnosis and management of hsPDA. Ourobjectives were to determine the diagnostic accuracy of BNP and NT-proBNP for hsPDA inpreterm neonates and to explore heterogeneity by analyzing subgroups.

METHODS: The systematic review was performed as recommended by the Cochrane Diagnostic TestAccuracy Working Group. Electronic databases, conference abstracts, and cross-references weresearched. We included studies that evaluated BNP or NT-proBNP (index test) in preterm neonateswith suspected hsPDA (participants) in comparison with echocardiogram (reference standard). Abivariate random effects model was used for meta-analysis, and summary receiver operatingcharacteristic curves were generated.

RESULTS: Ten BNP and 11 NT-proBNP studies were included. Studies varied by methodologicalquality, type of commercial assay, thresholds, age at testing, gestational age, and whether the assaywas used to initiate medical or surgical therapy. Sensitivity and specificity for BNP at summarypoint were 88% and 92%, respectively, and for NT-proBNP they were 90% and 84%, respectively.

CONCLUSIONS: The studies evaluating the diagnostic accuracy of BNP and NT-proBNP for hsPDAvaried widely by assay characteristics (assay kit and threshold) and patient characteristics(gestational and chronological age); therefore, generalizability between centers is not possible.We recommend that BNP or NT-proBNP assays be locally validated for specific patientpopulation and outcomes, to initiate therapy or follow response to therapy.

aSection of Neonatology and bDivision of Cardiology, Department of Pediatrics, Texas Children’s Hospital & Baylor College of Medicine, Houston, Texas; and cDepartment of ClinicalEpidemiology, Biostatistics and Bioinformatics, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands

Dr Kulkarni participated in the design, data acquisition, and interpretation and wrote the manuscript; Dr Gokulakrishnan participated in the design, data acquisition,analysis, and interpretation and assisted in writing the manuscript; Drs Price, Fernandes, and Leeflang provided critical intellectual input and revised the manuscript;and Dr Pammi conceived the project, participated in the design, data acquisition, analysis, and interpretation, and assisted in writing the manuscript.

www.pediatrics.org/cgi/doi/10.1542/peds.2014-1995

DOI: 10.1542/peds.2014-1995

Accepted for publication Nov 21, 2014

Address correspondence to Mohan Pammi, MD, PhD, 6621 Fannin, MC: WT 6-104, Houston, TX 77030. E-mail: [email protected]

PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).

Copyright © 2015 by the American Academy of Pediatrics

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

FUNDING: No external funding.

POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

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A symptomatic hemodynamicallysignificant PDA (hsPDA) is oftentreated medically or by surgicalclosure. Echocardiogram is the goldstandard for the diagnosis of hsPDA,but it is expensive and not alwaysavailable in resource-limited settings.A simple blood assay that candiagnose hsPDA reliably will beuseful to clinicians in such settings.

Brain natriuretic peptide (BNP) andamino-terminal pro-B-typenatriuretic peptide (NT-proBNP) aresynthesized and released into thecirculation by the cardiac ventricularmyocytes in response to pressureoverload, volume expansion, andincrease in myocardial wall stress.Within the myocytes, the precursorpro-BNP (108 amino acids) isconverted to the biologically activeform, BNP (77–108 amino acids) andthe inactive NT-proBNP fragment(1–76 amino acids). BNP improvesmyocardial relaxation and regulatesresponses to acute increases inventricular volume by opposing thevasoconstriction, sodium retention,and antidiuretic effects of theactivated renin-angiotensin-aldosterone system.1 Plasma BNP andNT-proBNP are cleared by the kidneysand hence elevated in patients withrenal failure. NT-proBNP has a longerhalf-life (60–120 minutes vs22 minutes2,3) and is more stablein vitro. BNP and NT-proBNP are well-established markers of heart failure inadults4,5 and children.6

Many commercial kits are availablefor assessment of BNP andNT-proBNP, and levels reported varywith chronological age, gestationalage (GA), PDA, and renal function.The normative values of BNP andNT-proBNP in neonates from variousstudies are presented inSupplemental Table 3. BNP andNT-proBNP values are highest in thefirst 3 days of life and declineprogressively thereafter.7,8 Levels inpreterm neonates are higher than infull-term neonates and are similar by1 month of life.9,10 NT-proBNP values

are 6 to 20 times higher than BNPvalues, and the ratio betweenNT-proBNP and BNP is influenced byage.11–17

BNP and NT-proBNP assays havebeen reported in the management ofmultiple neonatal conditionsincluding hsPDA.9,18–51 BNP andNT-proBNP have been used inpreterm neonates both for diagnosisand to initiate medical or surgicaltreatment of hsPDA. The diagnosticaccuracy of BNP and NT-proBNP inthe management of hsPDA inneonates has not been systematicallyreviewed.

Our primary objective was todetermine the diagnostic accuracy ofcardiac biomarkers BNP and NT-pro-BNP in the diagnosis of hsPDA inpreterm neonates.

The secondary objective was toexplore heterogeneity among studiesevaluating BNP and NT-proBNP byanalyzing the following subgroups:commercial assay, test threshold, ageof the patient at testing, GA at birth,and whether the test was used toinitiate medical or surgical treatment.

METHODS

The method recommended by theCochrane Diagnostic Test AccuracyWorking Group was followed (http://srdta.cochrane.org/). The title hasbeen registered with the CochraneNeonatal Review Group.

Criteria for Consideration of Studiesfor Review

Prospective and retrospective studiesthat evaluated blood BNP orNT-proBNP (index tests) in thediagnosis of PDA (target condition) inpreterm neonates in conjunction withan echocardiogram (referencestandard) were eligible for inclusion.Studies were excluded in whicha threshold was not reported or couldnot be obtained from the authors.

There is no consensus forechocardiographic criteria for hsPDA.We chose 2 echocardiographic

criteria to define hsPDA in preterminfants based on the best availableevidence: LA/Ao ratio .1.5 andductal diameter .1.5 mm (asmeasured by color Doppler), whichare early predictors of hsPDA.52

LA/Ao ratio is estimated from thediameter of the left atrium (LA) andfrom the aortic root diameter (Ao) inthe parasternal long-axis view at thelevel of the aortic valve.52–54

Search Strategy for Identification ofStudies

We searched the following sources inApril 2014 without any languagerestriction:

1. Electronic bibliographic databaseswere searched: Medline (1966 topresent) and Cumulative Index toNursing and Allied Health Litera-ture (CINAHL) (1982 to present).

2. Abstracts of conferences: pro-ceedings of pediatric academicsocieties (American PediatricSociety, Society for PediatricResearch, and European Societyfor Pediatric Research) weresearched from 1990 from thejournal Pediatric Research andabstracts2view.com online.

3. The Web of Science was searched.

4. PubMed’s related citations featureand relevant identified articleswere searched.

5. The Science Citation Index wasused to identify relevant articlesby using previously identifiedarticles.

6. Additional searches were madefrom reference lists in identifiedstudies.

The search strategy is described inSupplemental Appendix 1.

Data Collection and Analyses

Selection of Studies

All titles and abstracts identified byour search strategy were screened forrelevance by authors M.K. and M.P.together. All identified articles thatwere relevant to the review wereretrieved in full and evaluated for

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inclusion eligibility by M.P. and M.K.independently. The results werecompared and disagreements wereresolved by mutual discussion.

Data Extraction and Management

Data extracted included author, yearof publication and journal, studydesign, study population, referencestandard and performance of thereference standard, index tests andperformance of the index tests,information about quality assessmentitems based on Quality Assessment ofDiagnostic-Accuracy Studies(QUADAS-2),55 and data for 232tables. Additional information toclarify the study design and data wassought from the authors via e-mail for$3 attempts. All the data wereentered electronically on MicrosoftExcel (Microsoft Corp, Redmond, WA)spreadsheets by M.P. and M.K.independently. The data extracted byeach author were compared, and anydiscrepancies were resolved bymutual discussion and input fromauthor C.J.F.

Assessment of Methodological Quality

The methodological quality of eachstudy was assessed as recommendedby the Cochrane Diagnostic TestAccuracy Working Group adaptingfrom the QUADAS-2 by authors G.G.and M.K. The 4 domains assessed forrisk of bias were patient selection,index test, reference test, and flowand timing. Applicability concernswere assessed in the first 3 domains,as described in SupplementalAppendix 2. The data were thenentered into Review ManagerSoftware (RevMan 5.3; The CochraneCollaboration, Oxford, England) formeta-analysis and to generatefigures.56

Statistical Analyses and Data Synthesis

We constructed 232 tables for allstudies with the reference standardand index tests and enumerated true-positives, false-positives, false-negatives, and true-negatives for allthe reported thresholds. For the

studies that reported sensitivity andspecificity at defined thresholds,reverse calculation was done togenerate a 232 table. Data wereentered in RevMan 5.3, and forestplots with 95% confidence intervals(CIs) for sensitivity and specificity foreach study were created. Resultswere also plotted in the receiveroperating characteristic (ROC) spacewith 95% confidence estimates,summary point, and the summarycurve. The meta-analyses by bivariaterandom effects model wereperformed by using the metandipackage in the statistical softwareStata 11 (Stata Corp, College Station,TX). The following covariates wereevaluated: test assay kit, thresholds(as continuous), GA, chronological age

at the time of the test, and whetherused to initiate medical or surgicaltherapy.

Investigations of HeterogeneityAmong Studies

We investigated heterogeneitythrough subgroup analyses if datawere available from $4 studies:

1. Type of commercial test assayused for BNP and NT-proBNP, be-cause measurements may varywith each commercial assay.

2. Effects of age at testing: BNP andNT-proBNP levels are higher atbirth and then decline over time.

3. Effects of GA: BNP and NT-proBNPlevels are higher in preterminfants than in term infants.

FIGURE 1Inclusion process for the systematic review based on Preferred Reporting Items for SystematicReviews and Meta-Analyses. a Review articles, animal studies, and studies that did not reportoutcomes of interest (congenital heart disease, intraventricular hemorrhage, transient tachypnea ofthe newborn, hypoxic-ischemic encephalopathy, respiratory distress syndrome) or did not evaluateBNP or NT-proBNP. b Reasons for exclusion are listed in Table 2.

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TABLE 1 Characteristics of Included Studies

Study,Country

StudyDesign

Inclusion Criteria forParticipants’ and SummaryStatistic: GA (wk) or BW (g)

Index Test, Assay Kit,Threshold Cutoffs, andTiming of the Assay

Reference Standard Echocardiogram AreaUnder

the Curve

Included studies evaluating BNP1 Lee et al

2013,20

Korea

Retrospective BW ,1000 g BNP Symptomatic PDA: presence of 2 of thefollowing 5 signs with the confirmation ofa large L → R ductal flow byechocardiogram

0.830

Mean 6 SD Test kit: Triage, SanDiego

Clinical criteria

Control group Multiple: 864 pg/mL¥,100 pg/mL, 150 pg/mL,200 pg/mL, 400 pg/mL*,600 pg/mL, 900 pg/mL

• Systolic or continuous murmur

GA: 27.3 6 2.3 Timing: 24 h of life • Bounding pulse or a hyperactive precordialpulse

BW: 855 6 112 • Hypotension without response to loading fluidand infusion of dopamine

hsPDA group: • Worsening ventilator statusGA: 27.1 6 2.2 • Chest radiograph evidence: pulmonary

congestion or cardiomegaly(a cardiothoracic ratio .60%) withincreased pulmonary flow

BW: 819 6 123

2 Mine et al2013,21

Japan

Retrospective GA ,33 wk, BW ,1500 g BNP Echocardiogram at the time of admission andevery 12 h

0.68

Median and interquartilerange

Test kit: Shionospot,Osaka, Japan

• End-diastolic blood flow velocity of the leftpulmonary artery .30–40 cm/s

0.94

Control group 250 pg/mL* forindomethacintreatment

• Diastolic blood flow of the anterior cerebralartery interrupted

GA: 28.1 (25.5–29.2) wk 2000 pg/mL for surgicalligation

• Diastolic blood flow of the superiormesenteric artery interrupted

BW: 950 (799–1181) g Timing: 24–48 h of agehsPDA groupGA: 28.0 (27.0–29.2) wkBW: 960 (735–1137) g

3 Kim and Shim2012,19

Korea

Prospective GA ,37 wk BNP Echocardiographic criteria 0.998Mean 6 SD Test kit: Abbott, IL • LA/Ao .1.4Control group 412 pg/mL • Diastolic turbulence of pulmonary artery on

DopplerGA: 32.83 6 2.22 wk Timing: day 4 of life • Ductal diameter of PDA .1.4 mmBW: 1930 6 490 g PLUS 3/6 clinical signs

hsPDA group • Systolic/continuous murmurGA: 32.18 6 1.67 wk • Increased precordial pulseBW: 1850 6 480 g • Bounding peripheral pulses

• Resting tachycardia• Unexplained deterioration of respiratorystatus and increased vascular marking,heart enlargement, or pulmonary edema onchest radiograph

4 Elsayed et al2012,58

Canada

Prospective GA ,31 wk BNP Echocardiogram NAMean 6 SD Test kit: unknown • PDA diameter .1.5 mmNo PDA 90 pg/mL • L → R nonrestrictive shuntGA: 29.3 6 1.0 wk Timing: 48–72 h of ageBW: 1325 6 261 g

Non-hsPDAGA: 28.2 6 1.7 wkBW: 1160 6 257 g

hsPDAGA: 26.9 6 1.4 wkBW: 925 6 209 g


TABLE 1 Continued

Study,Country

StudyDesign




the Curve

5 Elsayed et al2011,57

Canada

Prospective GA ,31 wk BNP and PDA score Echocardiogram NAMean (6SD) Test kit: unknown • PDA diameter .1.5 mmNon-hsPDA group 90 pg/mL and PDA

score .7• L → R nonrestrictive shunt

GA: 28.6 6 1.1 wk Timing: 48–72 h of ageBW: 1270 6 27 g

hsPDA groupGA: 26.7 6 1.2 wkBW: 897 6 16 g

6 Kalra et al2011,18 USA

Prospective BW ,1250 g, GA ,34 wkwith normal renalfunction

BNP Echocardiogram 1.00

Did not describe thedemographics of thepatient population

Test kit: Triage, SanDiego

PDA was reported as no, small, moderate, orlarge based on ductal diameter at thepulmonary side, absolute size of the PDA incomparison with the branch pulmonaryarteries. Secondary considerations werelength of color flow jet into the mainpulmonary artery, presence of diastolicreversal of flow in the descending aorta, andthe presence of left atrial and ventriculardilatation including LA/Ao ratio.

123 ng/L or pg/mLTiming: between days3 and 7

7 Chen et al2010,22 USA

Retrospective GA 24–32 wk with $1BNP–echocardiogrampair (done on same day)

BNP Echocardiogram 0.85

Mean 6 SD Test kit: Triage, SanDiego

• Ductus diameter .1.5 mm

GA: 27.3 6 2.1 wk Multiple cutoffs: 40 pg/mL¥,60 pg/mL, 80 pg/mL,100 pg/mL*, 200 pg/mL,and 300 pg/mL formoderate–large PDAand large PDA

• LA/Ao .1.5

BW: 980 6 276 g Timing: variable • Diastolic flow velocity in the left pulmonaryartery .0.2 m/s and

• Presence of holodiastolic reversal of flow inthe descending aorta (at the level of thediaphragm)

8 Czernik et al2008,24

Germany

Prospective GA ,28 wk BNP Echocardiogram showing 0.86Median (interquartilerange)

Test kit: ADVIA Centaur,Germany

• Narrowest ductal diameter .2 mm

Control group Multiple cutoffs:550 pg/mL¥ predictductus intervention.Others were 380 pg/mL,450 pg/mL, 500 pg/mL*,600 pg/mL, and650 pg/mL.

• PDA with L → R shunt

GA: 26 (25–27) wk Timing: second day oflife

• Need for ventilatory supportBW: 948 (720–1100) g

hsPDA groupGA: 25 (24–26) wkBW: 737 (650–827) g


TABLE 1 Continued

Study,Country

StudyDesign




the Curve

9 Sanjeev et al2005,25 USA

Prospective BW 500–1500 g BNP Echocardiogram 0.91Mean 6 SD Test kit: Triage, San

Diego, CA• LA/Ao .1.4, LV/Ao .2.1

GA: 26 6 2 wk Multiple cutoffs:70 pg/mL¥, 50 pg/mL,60 pg/mL, 80 pg/mL,90 pg/mL*, 100 pg/mL

• Narrowest ductal diameter .1.5 mm

BW: 873.5 6 247 g Timing: variable10 Choi et al

2005,26

Korea

Prospective GA 25–34 wk BNP Symptomatic PDA: presence of 2 of thefollowing 5 signs with the confirmation ofa large L → R ductal flow byechocardiogram

0.997

Mean 6 SD Test kit: Triage, SanDiego, CA

Clinical criteria

Control group Multiple cutoffs:1110 pg/mL and1295 pg/mL

• Systolic or continuous murmur

GA: 30.3 6 2.4 wk Timing: day 3 • Bounding pulse or a hyperactive precordialpulse

BW: 1396 6 418 g • Hypotension without response to loading fluidand infusion of dopamine

hsPDA group • Worsening ventilator statusGA: 29.1 6 2.75 wk Radiographic evidence: pulmonary congestion

or cardiomegaly (a cardiothoracic ratio.60%) with increased pulmonary flow

BW: 1283 6 359 g

Included studies evaluating NT-proBNP1 Occhipinti et al

2014,74 ItalyProspective GA 23–32 wk NT-proBNP • Ductal diameter/birth wt ratio .1.4 or 0.86

Mean 6 SD Test kit: Roche Elecsys,Germany

• LA/Ao ratio.1.4 or

GA: 28.3 (62.6) wk 9854 pg/mL • Pulsatile flow patternBW: 1085 (6365) g Timing: 6–24 h of life

2 Buddhe et al2012,60 USA

Prospective BW ,1500 g NT-proBNP PDA size.1 mm with$2 additional features ofPDA

0.98

Mean 6 SD Test kit: VITROS NT-proBNP reagent pack

• Continuous murmur

Control group 5900 pg/mL • Pulse pressure .25 mm HgGA: 28.0 (62.4) wk Timing: day 3–5 of life • Worsening respiratory statusBW: 1053 (6278) g • LA/Ao ratio .1.4

hsPDA group • Resistive index of SMA calculated as peaksystolic velocity 2 end diastolic velocity/time averaged mean velocity .6

GA: 26.6 (62.7) wk • Base excess .25BW: 829 (6276) g

3 Cambonie et al2012,27

France

Prospective GA ,32 wk withrespiratory distressnecessitating invasivemechanical ventilationand surfactant

NT-proBNP Echocardiogram showing PDA and $2 of thefollowing criteria:

0.87

Mean 6 SD Test kit: RxL Dimension,Siemens, Newark, NJ

• LA ⁄Ao ratio .1.48

Control group 8500 pg/mL • Retrograde or absent diastolic flow in the ACAor SMA

GA: 29.5 (62.2) wk Timing: 24–72 h of life • Growing or pulsatile pattern flow in the DABW: 1256 (6397) g • End-diastolic flow velocity in the LPA.0.20 m⁄s

hsPDA group Requirement of invasive ventilation withfraction of inspired oxygen .0.3 aftersurfactant treatment or invasive ventilationplus catecholamine use for severehypotension

GA: 27.5 (62.2) wkBW: 962 (6275) g


TABLE 1 Continued

Study,Country

StudyDesign




the Curve

4 Letzner et al2012,38

Switzerland

Prospective GA ,32 wk NT-proBNP • Presence of PDA with L→ R shunting 0.64Median (5%–95% range) Test kit: BRAHMS

KRYPTOR, Germany• Narrowest ductal diameter $1.5 mm and

Control group 2316 pg/mL on day 0 • LA/Ao ratio $1.5 andGA: 30.7 (26.2–31.9) wk 10 253 pg/mL on day

2–3• Diastolic retrograde flow in the postductal

descending aortaBW: 1400 (806–2011) g

hsPDA groupGA: 28 (24.7–31.6) wkBW: 960 (573–1797) g

5 Letshwiti et al2011,61

Ireland

Prospective BW ,1500 g NT-proBNP • Ductal diameter .2 mm 0.93Mean 6 SD Test kit: Roche Elecsys,

GermanyGA: 28.3 (62.5) wk 3587 ng/L = 3587 pg/mLBW: 1115 (6255) g Timing: day 7 of life

6 Martinoviciet al 2011,28

Belgium

Prospective GA ,32 wk or BW ,1500 g NT-proBNP Echocardiograms on days 4 and 7 of life 0.92Mean 6 SD Test kit: Roche Elecsys,

Germany• Ratio of ductal diameter to birth wt (DA/kg in

mm/kg) .1.4 and0.98

Control group 10 000 pg/mL on day 2 • LA/Ao .1.4GA: 29.8 6 2.2 wk 5000 pg/mL * on day 4BW: 1290 6 360 g

hsPDA groupGA: 28.0 6 1.7 wkBW: 1080 6 350 g

7 Deorari et al2011,59 India

Prospective GA#32 wk and BW,1500 g NT-proBNP Echocardiogram on days 1, 3, and 7 0.8Mean 6 SD Test kit: Roche Elecsys,

GermanyDuct size $1.5 mm along with one of the

following criteria:GA: 30.3 6 1.6 wk 17 984 pg/mL • LA/Ao ratio $1.5 orBW: 1090 6 237 g Timing: 72 6 12 h of

life• Absent or retrograde flow in descending

aorta8 Ramakrishnan

et al 2009,30

UK

Prospective GA 23–34 wk NT-proBNP Echocardiogram between day 5 and 7 and afterPDA treatment

0.897

Mean 6 SD Test kit: Roche Elecsys,Germany

• LA/AO ratio .1.5 and

GA: 28.2 6 2.8 wk Multiple cutoffs:2850 pmol/L =24 102 pg/mL *,1280 pmol/L =10 825 pg/mL,5160 pmol/L =43 638 pg/mL

• Duct diameter .1.5 mm

BW: 1162 6 482 g Timing: day 3 of life9 Nuntnarumit

et al 2009,10

Thailand

Prospective GA ,33 wk NT-proBNP Echocardiogram on days 2, 4, and 7 andwhenever hsPDA suspected

0.964

Median (interquartilerange)

Test kit: Roche Elecsys,Germany

Ductal flow with predominant L → R on colorDoppler that measured $1.5 mm on2-dimensional echocardiogram, plus $2 ofthe following signs:

Control group 10 180 pg/mL • Heart murmurGA: 31 (28–33) wk Timing: day 2 of life • Persistent tachycardia (heart rate

.160/min)BW: 1360 (730–1830) g • Hyperactive precordium

hsPDA group • Bounding pulse, pulse pressure .25 mm HgGA: 29 (27–31) wk • HepatomegalyBW: 1250 (925–1540) g • Pulmonary hemorrhage

• Increasing respiratory support by 20%increase in oxygen supplementation or inpressure support and

• Radiographic evidence of cardiomegaly orpulmonary congestion


4. We determined whether theresults of the test were used toinitiate medical or surgical treat-ment of PDA.

5. Assay threshold cutoffs vary withthe commercial assay and patientcharacteristics such as GA andchronological age.

RESULTS

We identified 82 records throughdatabase searches and 21 additionalarticles from conference abstractsand cross-referencing. The inclusionprocess is detailed in the PreferredReporting Items for SystematicReviews and Meta-Analyses flowdiagram (Fig 1). Ten studies thatevaluated BNP and 11 studies thatevaluated NT-proBNP in thediagnosis of hsPDA met our inclusioncriteria (Table 1). Excluded studiesand reasons for exclusion aredescribed in Table 2.

Methodological assessment ofincluded studies revealed study

deficiencies in the following domains(Fig 2, Supplemental Figs 5 and 6):

1. Patient selection: Exclusion criteriain the individual studies were var-iable and were not defined in somestudies, which may have in-troduced bias.30,57–59 Some studieswere retrospective in design.16–18

Inclusion criteria differed, and allstudies except 119 had restrictiveinclusion criteria by birth weight(BW) and GA. Additional inclusioncriteria included presence of re-spiratory distress necessitatingmechanical ventilation and surfac-tant27 and BNP echocardiogramperformed on the same day,22

which might have excluded someeligible patients with hsPDA.

2. Index test: No study had a pre-defined threshold, and somestudies did not blind theclinician.10,19,22,25,26,59–61 Elsayedet al57,58 used BNP in addition toa clinical PDA score as the indextest. The PDA score incorporatedechocardiographic parameters

reflective of both volume and pres-sure overload (maximum score 15),and clinical, radiologic, and labora-tory features of both pulmonaryovercirculation and systemic hypo-perfusion (maximum score 13).

3. Reference standard: All studiesused an acceptable referencestandard, the echocardiogram, butechocardiogram criteria to definehsPDA were variable, which mayintroduce bias. There was absenceof blinding of the cardiologists tothe BNP assay in a fewstudies.10,19,26,57,59–61

4. Flow and timing: We noted longeror unclear time intervals betweenthe blood test (index test) andechocardiogram (reference stan-dard) in some studies, most nota-bly in the study by Kim and Shim,19

where time interval between theindex and reference standard wasas long as 48 hours.

Estimated summary sensitivity forstudies evaluating BNP was 0.88(95% CI, 0.76–0.95) and for

TABLE 1 Continued

Study,Country

StudyDesign




the Curve

10 Farombi-Oghuvbuet al 2008,37

Ireland

Prospective GA,34 wk and BW,2.0 kg NT proBNP Echocardiogram on days 1, 3, 5, and 10 of life 0.978Median (range) Test kit: Roche Elecsys,

Germany• Large ductal flow with L → R shunt

GA: 30 (24–33) wk 11 395 pg/mL • Ductal diameter .1.6 mm with retrogradeflow in the descending aorta

BW: 1220 (550–1950) g Timing: day 3 of lifeMedianControl groupGA: 30 wkBW: 1420 g

hsPDA groupGA: 26 wkBW: 1000 g

11 El-Khuffashet al 2007,31

Ireland

Prospective BW ,1500 g NT-proBNP: at 12 h andday 3 of life

Echocardiogram at 12 h, day 3, days 5–6, andafter PDA treatment

0.866

Median (interquartilerange)

Test kit: Roche Elecsys,Germany

• Ductal diameter .1.5 mm

Control group 5000 pmol/L = 42 285pg/mL

• LA/Ao .1.5

GA: 28 (26.1–29.5) wk Timing: day 3 of lifeBW: 1121 (948–1253) g

hsPDA groupGA: 27 (25.9–28.3) wkBW: 980 (823–1220) g

ACA, anterior cerebral artery; DA, ductus arteriosus; LPA, left pulmonary artery; SMA, superior mesenteric artery.* Threshold level used in the Forest plots and ROC analysis when using only one value per study;¥ Threshold level chosen by the authors for individual ROC analysis.



NT-proBNP was 0.90 (95% CI,0.79–0.96). Summary specificity forstudies evaluating BNP was 0.92(95% CI, 0.81–0.97) and forNT-proBNP 0.84 (95% CI, 0.77–0.90).Forest plots based on a singlethreshold from each study show thatsensitivity across studies ranged from0.60 to 1.0 for BNP and 0.58 to 1.0 forNT-proBNP, and specificity rangedfrom 0.6 to 1.0 for BNP and 0.57 to1.0 for NT-proBNP (Fig 3). We alsoplotted the included studies in theROC space to give a sense of thedistribution of the sensitivity andspecificity of the studies (Fig 4). Wereport the summary ROC curve,summary estimates of specificity and

sensitivity, and the 95% confidenceregions.

We analyzed subgroups of studiesevaluating BNP and NT-proBNPbased on the type of test kit, age attesting, and whether used to initiatemedical or surgical treatment, andsummary estimates are shown inSupplemental Table 4 andSupplemental Figs 7 and 8. Summaryestimates by meta-analysis werepossible only if $4 studies wereavailable in the subgroup. Only 1 testkit and only day 3 of testing had .4studies for both BNP and NT-proBNP.Only 2 studies evaluated BNP forsurgical closure of the ductus andnone for NT-proBNP. We could not

explore heterogeneity associated withgestational age or threshold cutoffsbecause of insufficient data and thelarge variability among studies,respectively.

DISCUSSION

We synthesized data from 21 studiesby meta-analysis; 10 evaluated BNPand 1 evaluated NT-proBNP in thediagnosis of hsPDA in pretermneonates. Estimated summarysensitivity for BNP was 0.88 (95% CI,0.76–0.95), and summary specificitywas 0.92 (95% CI, 0.81–0.97).However, there was wide variation insensitivity and specificity, and 2 of the10 studies, at the reported thresholds,reported sensitivity ,0.7.20,21 Mineet al21 described 2 thresholds in theirstudy: 250 pg/mL for indomethacintreatment with sensitivity of 0.60(95% CI, 0.36–0.81) and 2000 pg/mLfor the surgical treatment of PDA withsensitivity of 1.00 (95% CI, 0.4–1.00),both with wide 95% CIs. Conversely,Lee et al20 described sensitivity andspecificity at a range of thresholds and,at a chosen threshold of 864 pg/mL,had a high specificity 0.95 (95% CI,0.84–0.99) but low sensitivity at 0.55(95% CI, 0.36–0.73). One outlier wasthe threshold given by Mine et alfor indomethacin unresponsivenessand surgical indication with100% sensitivity at a high level of2000 pg/mL.21

The summary sensitivity forNT-proBNP was 0.90 (95% CI,0.79–0.96), and summary specificitywas 0.84 (95% CI, 0.77–0.90). In the11 included studies that evaluatedNT-proBNP, there was less variation insensitivity and specificity ofNT-proBNP when compared with BNPin the detection of hsPDA. In 2 of the11 studies, sensitivity was ,0.734,38

because they used a higher threshold.40 000 pg/mL. Letshwiti et al61

described a much lower threshold(3587 pg/mL) than El Khuffash andMolloy34 (42 285 pg/mL) orRamakrishnan et al30 (24 102 pg/mL)but had 100% sensitivity with narrow

TABLE 2 Characteristics of Excluded Studies

Excluded Study Assay Reason for Exclusion

1 Attridge et al 200945 BNP BNP to optimize indomethacin treatmentand not for the diagnosis of PDA

2 da Graca et al 200646 BNP No cutoff threshold reported3 Elsayed et al 201375 BNP Included patients with PDA only and used

BNP to predict failure of medical therapy4 Elsayed et al 201376 BNP Correlation of BNP and regional blood flow

in PDA and for the diagnosis of PDA5 Flynn et al 200548 BNP Insufficient data for 232 table; BNP

.300 pg/mL predicted significant PDA6 Hammerman et al 201241 BNP and NT-proBNP Review article7 Hollinger et al 201177 BNP No cutoff threshold reported8 Holmström et al 200149 BNP Insufficient data for 232 table9 Hsu et al 201023 BNP Included patients with PDA and used BNP to

predict indomethacin responsiveness10 Jeevananthan et al 201178 BNP Insufficient data for 232 table11 Kazanci et al 201279 BNP No cutoff threshold reported12 Mannarino et al 201044 BNP Compared BNP in term versus preterm

infants13 Perugu et al 201180 BNP BNP and other markers for ventricular

function in extremely low birth weightinfants and not for the diagnosis of PDA

14 Puddy et al 200247 BNP No cutoff threshold reported15 Tauber et al 201381 BNP No cutoff threshold reported16 Bagnoli et al 201040 NT-proBNP No cutoff threshold reported17 Celik et al 201282 NT-proBNP Urine levels of the natriuretic peptide18 Czernik et al 201351 NT-proBNP Urine levels of the natriuretic peptide19 El Khuffash et al 200833 NT-proBNP Used to predict which infants with PDA will

suffer death or intraventricularhemorrhage

20 El Khuffash et al 201183 NT-proBNP No outcome of interest reported21 Hammerman et al 201042 NT-proBNP Included patients with hsPDA only, used

percentage drop in NT-proBNP to predictresponse to treatment

22 Nuntnarumit et al 201136 NT-proBNP Used a predefined cutoff from previousstudy10 for early targeted treatmentwith indomethacin

23 Sellmer et al 201184 NT-proBNP No cutoff threshold reported24 Tosse et al 201239 NT-proBNP Urine levels of the natriuretic peptide25 Yildrim et al 201085 NT-proBNP No cutoff threshold reported




confidence intervals (95% CI,0.83–1.00). The cutoffs in this studymay be lower because of evaluation onday 7, when a physiologic decline inNT-proBNP levels is to beexpected.7,62,63

We assessed the methodologicalquality of studies by using the 4domains of the QUADAS-2 checklist:patient selection, index test, referencestandard, and flow and timing.Overall, most studies scored as low orunclear for risk of bias and

applicability concerns. All studiesenrolled preterm neonates, but someof them were more restrictive thanothers. BNP levels vary by GA, andthis could affect threshold valuesused to diagnose hsPDA. Some of thestudies have additional inclusioncriteria, such as ventilator supportand surfactant,27 and these criteriamight introduce applicabilityconcerns. Failure to report exclusioncriteria or variable exclusion criteriamay add bias.30,57–59 Three studies

had a retrospective design but hadcomparable inclusion and exclusioncriteria and definition for hsPDA.20–22

As described by Zonnenberg and deWaal,64 there were wide variations inthe definition of hsPDA in theincluded studies. This raisesapplicability concerns becausea neonate with hsPDA in 1 study maybe labeled as non-hsPDA in another.All the included studies evaluatingNT-proBNP were prospective indesign and more uniform in respectto inclusion criteria based on GAcompared with studies evaluatingBNP. One of the included studies (Kimand Shim19) reported the timeinterval of up to 48 hours betweenthe index test and the referencestandard. Because the half-life of BNPis 22 minutes and that of NT-proBNPis 60 to 120 minutes, changes in thephysiologic status at such long timeintervals may decrease thecomparability of the index andreference tests.2,3

Elsayed et al57,58 used a clinical PDAscore in addition to BNP levels for anROC analysis. The clinical PDA scoreincorporated echocardiographicparameters reflective of both volume

FIGURE 2Risk of bias and applicability concerns graph based on QUADAS-2. Methodological assessment ofincluded studies by QUADAS-2 method is presented. Review authors’ judgments about each domain forrisk of bias and applicability concerns presented as percentages across included studies: BNP (1stpanel; 10 studies) and NT-proBNP (2nd panel; 11 studies). Studies with high risk of bias and appli-cability concerns are shown in red, those that are unclear in yellow, and those with low risk in green.

FIGURE 3Sensitivity and specificity forest plots for BNP and NT-proBNP. This figure shows the forest plots of sensitivity and specificity along with covariates of assay typeand threshold for BNP and NT-proBNP studies choosing a single threshold, ordered alphabetically. Each study is shown in a row, with the study year, TP, truepositives; FP, false positives; FN, false negatives; TN, true negatives; assay, threshold, age, and sensitivity and specificity (blue squares) with 95% CI (black bars).


and pressure overload (maximumscore 15) and clinical, radiologic, andlaboratory features of bothpulmonary overcirculation andsystemic hypoperfusion.65 Inaddition, only 34 of 90 eligibleneonates were recruited in the study.A sensitivity analysis excluding the2 studies by Elsayed et al57,58 withunknown test kits, unknownexclusion criteria, PDA scores, andunaccountable total patients did notchange our summary estimates ofsensitivity and specificity significantly(summary sensitivity [0.87 vs 0.88]and specificity [0.89 vs 0.92]).

We attempted to exploreheterogeneity on the basis of type ofassay kit, age at testing, gestational

age, threshold cutoffs, and whetherindicated for medical or surgicalclosure. Data were insufficient to makeany meaningful comparisons. Therewere wide variations in the thresholdcutoffs in studies on BNP as well asNT-proBNP, possibly because ofdifferences in assay characteristics orpatient characteristics, which precluderecommendation of a specificthreshold value of BNP or NT-proBNPfor the diagnosis of hsPDA.

BNP and NT-proBNP assays arewidely available and used in childrenand adults, both in hospitals and inthe community, to diagnose ormonitor cardiac failure in at-riskpatients.66–68 Many studies of BNPand NT-proBNP have been reported

from the developing countries, inresource-limited settings.10,38,59 Theeasy availability and its potential tocomplement echocardiography in thediagnosis of hsPDA or cardiacdysfunction in patients withbronchopulmonary dysplasia is likelyto increase its usage in neonatal units,especially in resource-limited areas.In adults, serial NT-proBNPestimations to guide therapy decreasemortality and hospitalization anddecrease health care costs.68–71

However, studies that evaluatedcost-effectiveness of BNP orNT-proBNP have not been reported inthe neonatal population.

Strength and Weaknesses of theReview

Strengths

Our systematic review follows themethod recommended by theCochrane Diagnostic Test AccuracyWorking Group. We searchedcomprehensively for all eligiblestudies by using clinically relevantinclusion criteria. We used thebivariate random effects model formeta-analyses of the included studiesand strove to explain the sources ofheterogeneity by subgroup analysesbased on type of commercial assay,test threshold, age of the patient attesting, gestational age, and whetherused for medical or surgicaltreatment of the PDA.

Weaknesses

Unlike meta-analyses of randomizedcontrol trials, heterogeneity is a well-recognized problem in reviews ofdiagnostic test accuracy.72 Despiteour extensive search strategy, we mayhave missed potential studies,because diagnostic accuracy studiesare poorly tagged in electronicdatabases. Publication bias in studiesreporting diagnostic test accuracy hasbeen poorly studied.73 Poor reportingof study design, method ofenrollment, and patientcharacteristics may hampermethodological assessment andexternal validity of the studies.

FIGURE 4Studies of BNP and NT-proBNP are plotted in the ROC space. BNP studies are represented in blueovals, NT-proBNP in red diamonds, and the size of the study symbols weighted for sample size. Thesummary curves (black line for BNP and red for NT-proBNP), summary points (black dot for BNP andred for NT-proBNP), and the 95% confidence region (dotted line) were derived from meta-analyses.Summary estimates at the summary point are as follows: BNP, sensitivity 88% and specificity 92%;NT-proBNP, sensitivity 90% and specificity 84%.


Another limitation of our reviewmight be that echocardiogram(reference standard) parameters todiagnose hsPDA were not consistentbetween studies. A systematic reviewof the definition of hsPDA byechocardiogram highlights this issuein detail.64 An ideal referencestandard in the diagnosis of hsPDAmay be a composite ofechocardiographic, clinical, andradiographic findings, which must beevaluated and validated.

Applicability of Findings to ClinicalPractice and Policy

New diagnostic tests can assume thefollowing roles in a diagnosticpathway: replacement of the existingtest, triage, or add-on to an existingtest. In the context of hsPDA, it is notreasonable to replace theechocardiogram with BNP orNT-proBNP testing. The standard ofcare is to confirm the presence ofhsPDA and rule out ductal-dependentlesions with an echocardiogrambefore initiating therapy. BNP andNT-proBNP testing may be useful totriage cases of suspected hsPDA todecrease the need forechocardiograms, especially inresource-poor settings. A sensitivityof .85% would be preferable in thissetting, where echocardiogram wouldbe indicated if the BNP or NT-proBNPassay exceeds the threshold cutoff. In100 preterm neonates with hsPDA,we would miss 15 neonates after BNPor NT-proBNP assay. Serialestimations dictated by the clinicalcondition may diagnose hsPDA in themissed neonates. BNP or NT-proBNPlevels do not decline with theworsening or persistence of hsPDA,and echocardiogram can beperformed later. A decrease in theneed for echocardiograms willdecrease use of resources, includingpersonnel and equipment, in additionto avoiding patient discomfort. Thisdecrease can have a huge impact onthe health care costs because the costof 1 echocardiogram is .10 times thecost of a BNP or NT-proBNP test. BNP

can also be used as an add-on test toechocardiogram and has theadvantage of serial testing for trendsbefore or after initiating medicaltherapy to guide managementwithout the need for serialechocardiograms.10,23,26,28,30

Threshold cutoffs should be based onthe normative values at differentgestational and chronological ages,validated locally for the type ofcommercial assay used and thepatient population being investigated.Costs of the BNP and NT-proBNPassays must be balanced with itsability to affect clinical outcomesbefore widespread acceptance inclinical practice.

CONCLUSIONS

We found wide variability in thediagnostic accuracy of BNP and NT-proBNP in the diagnosis of hsPDA inneonates. Heterogeneity in testresults may result from both thecharacteristics of the assay (type ofassay or thresholds used) and patientcharacteristics (gestational andchronological age), and thereforegeneralizability is limited. Werecommend that the type of assayshould be locally validated in thespecified population for the specifiedoutcome (to initiate therapy or followresponse after therapy) for diagnosticaccuracy before use to guide clinicaldecisions.

Future studies should be designedsatisfying the methodological qualityitems expounded in the QUADAS-2evaluation system, so that studies areof high methodological quality withminimal bias. Studies reportingdiagnostic test accuracy shouldexplicitly state the method ofenrollment (prospective orretrospective), characteristics of thepopulation assessed (eg, gestationalage, birth weight, comorbidity),blinding of reference standard andindex tests, and explanation ofwithdrawals. There is a real need forinternational consensus on defininghsPDA based on echocardiographic

and objective clinical parameters.Studies should explicitly state thedetails of the clinical setting andpatient characteristics so thatclinicians can determine thegeneralizability of the diagnostic testto their patient population. Acomposite scoring system thatincludes gestational andchronological age-specific BNP valuesand clinical parameters may improvediagnostic accuracy andgeneralizability but needs evaluation.

ACKNOWLEDGMENTS

We acknowledge the followinginvestigators for providing data fortheir studies: Maria Pia de Carolis, JanMiletin, Johannes Letshwiti, GillesCambonie, Sven Wellmann,J. B. Letzner, Henrik Holmstrom,Atsushi Ohashi (K Mine), Arun Sasi,and Afif El-Khuffash.

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