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Diagnosis, Evaluation, and Management of Patent Ductus Arteriosus in Preterm

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DOI: 10.1001/jamapediatrics.2015.0987 · Source: PubMed

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 Clinical Review & Education

Review

Diagnosis, Evaluation, and Management

of Patent Ductus Arteriosus in Preterm Neonates
Amish Jain, MBBS, MRCPCH; Prakesh S. Shah, MD, MSc, FRCPC

Patent ductus arteriosus (PDA) poses a diagnostic and therapeutic dilemma for clinicians.
Diagnosis of persistent PDA and determination of its clinical and hemodynamic significance
are challenging. Although the condition has been associated with substantial neonatal
morbidities such as intraventricular hemorrhage, bronchopulmonary dysplasia, and
necrotizing enterocolitis, most therapeutic approaches have failed to show improvement in
these outcomes. As such, clinicians have tended toward conservative management
strategies; however, the benefits and risks of such an approach are unclear. In this review, we
explore various clinical diagnostic modalities, echocardiographic parameters for assessment
of shunt presence, shunt volume and its effect on cardiovascular and hemodynamic status,
and challenges in determining if a PDA is hemodynamically significant and clinically relevant.
Author Affiliations: Department of
From the therapeutic aspect, we review current evidence on conservative, pharmacological, Paediatrics, Mount Sinai Hospital, and
and mechanical (surgical or nonsurgical ligation) approaches to PDA closure. Dose, route, University of Toronto, Toronto,
duration, and comparison of pharmacological strategies are reviewed, with implications for Ontario, Canada.
future research. Corresponding Author: Prakesh S.
Shah, MD, MSc, FRCPC, Department
of Paediatrics, Mount Sinai Hospital,
JAMA Pediatr. doi:10.1001/jamapediatrics.2015.0987 Room 19-231F, 600 University Ave,
Published online July 13, 2015. Toronto, ON M5G 1X5, Canada
(pshah@mtsinai.on.ca).

D
iagnosis and management of patent ductus arteriosus
(PDA) in preterm neonates represent a highly debated
topic. Physiological studies have shown several hemody-
namic alterations that normalize after successful ductal closure. Epi-
demiological studies have also demonstrated significant associa-
tions between a large PDA and neonatal outcomes, including
intraventricular hemorrhage (IVH), bronchopulmonary dysplasia
(BPD), necrotizing enterocolitis (NEC), and mortality. However, trials
of treatment to date have not shown improvements in outcomes.
Variability in approaches to evaluation and management of PDA has
been suggested as one explanation for these inconsistent findings.
In this review, we summarize evidence for PDA diagnosis methods
and appraise the currently available therapeutic interventions.
Diagnosis and Evaluation
Clinical Examination
A clinical diagnosis of PDA in preterm neonates is typically made ac-
cording to a high index of suspicion and the presence of 1 or more
characteristic clinical signs. In several cases, a PDA shunt has been
shown to be already left to right and of high volume as early as 6
hours of age.1 However, typical clinical signs are absent at this early
stage. Furthermore, exclusive use of clinical signs for diagnosing PDA
during the first week after birth has limitations (Table 1), with poor
to moderate interobserver agreement.2-7 Lower blood pressures are
the only consistently reported clinical finding associated with a large
PDA on day 1 after birth.4 This lag is due to the lower shunt velocity
and delayed adaptation of the immature myocardium to changes in
preload. An increase in shunt velocity coinciding with declining pul-
monary vascular resistance produces a characteristic systolic
murmur.7 Subsequent myocardial adaptation leads to tachycardia,
increased stroke output, and contractility, which manifest clinically
as hyperactive precordium, increased pulse volume, and wide pulse
pressure. A chest radiograph may also reveal signs of pulmonary over-
circulation and left heart dilatation. Among clinical signs, the pres-
ence of a murmur has the highest specificity for the presence of a
PDA but lacks sensitivity. The study7 by Skelton et al reported that
a murmur was heard in 11% of neonates with closed ducts and in 24%
with a small PDA, indicating that isolated use of this clinical sign to
diagnose a large PDA can lead to significant misclassification.
Echocardiography
Although an initial PDA diagnosis typically involves clinical signs, ech-
ocardiography is the gold standard and is used for direct assess-
ment of PDA diameter and shunt pattern, as well as indirect assess-
ment of shunt volume, for which several surrogate measures have
been proposed (Table 2). For hemodynamically significant PDAs,
echocardiographic signs have been shown to precede clinical rec-
ognition by 1.8 days.7
PDA Diameter and Shunt Pattern
Patent ductus arteriosus diameter is measured at its narrowest part
in end systole and can be expressed either as an absolute value in
millimeters or indexed to the diameter of the left pulmonary artery
(the ratio of PDA to LPA) or patient body weight (in millimeters per
kilogram).8-10 However, the relative benefit of each approach is un-
known. Shunt pattern assessment includes establishing direction-
ality and velocity during systole and diastole. For a PDA to cause sig-
nificant shunting from systemic to pulmonary circulation, the flow

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 Clinical Review & Education Review
needs to be unrestrictive and completely or almost completely left
to right; the latter is sometimes referred to as a growing pattern.11
The PDAs of less than 1.5 mm in diameter are considered small
because they are commonly restrictive, cause a mild increase in pul-
monary circulation, and are rarely associated with echocardio-
graphic markers of a high-volume shunt.12,13 Further subclassifica-
tion of PDAs of at least 1.5 mm as moderate or large is based on
incremental probability of a high-volume shunt. Although the di-
ameter correlates well with shunt volume, using an absolute cutoff
to describe hemodynamic significance may be misleading given the
interobserver measurement variability (10%-15%) and its dynamic
nature.
Shunt Volume
Direct calculation of shunt volume is not feasible, so it is com-
monly estimated using surrogate indexes.14 A left-to-right, high-
volume PDA shunt causes an increase in antegrade total and dia-
stolic blood flow in branch pulmonary arteries, left atrial and left
ventricle end-filling dimensions, mitral valve inflow, and compen-
satory changes in left ventricle hemodynamics. In the presence of
an isolated ductal shunt, the right ventricular output is reflective
of systemic blood flow, whereas the left ventricular output equals
pulmonary blood flow.
Lack of standardized measures limits the interpretation of vali-
dation studies1,8,12,13,15-20 involving echocardiographic indexes
(Table 3). Only 3 studies to date have reported on some measure of
pulmonary blood flow, including (1) the ratio of echocardiography-
derived right and left ventricular stroke volumes in the absence of
a significant interatrial shunt,19 (2) the ratio of left ventricular out-
put to superior vena cava flow (a ratio ⱖ4 is likely associated with
a 50% increase in pulmonary blood flow from the PDA),8 and
(3) phase-contrast magnetic resonance imaging–derived left ven-
tricular output, superior vena cava flow, and flow in the postductal
descending aorta.17 Correlations between these markers are weak
to moderate, with a significant overlap between cases and con-
trols. Diastolic flow reversal in the descending aorta appears to be
the most consistent feature of a high-volume PDA shunt.
Early Prediction of Hemodynamically Significant PDA
Echocardiography indexes have also been used to identify PDAs that
are likely to become hemodynamically significant (Table 4).9-11,21,22
However, the reported sensitivities and specificities ranged from
26% to 100% and from 6% to 100%, respectively.
Biomarkers
A more recent development in PDA evaluation is the use of serum
biomarkers, in particular brain-type natriuretic peptide (BNP) and
N-terminal pro-BNP (NTpBNP).23,24 The inactive precursor pro-
BNP is released from ventricles in response to pressure or volume
overload and then cleaved into the metabolically active BNP and in-
active metabolite, NTpBNP. The results of studies24-26 have sug-
gested that after the first 48 hours of age in preterm neonates the
concentration of both of these biomarkers increases with the emer-
gence of hemodynamically significant PDA and decreases with suc-
cessful PDA closure; however, there was wide interstudy variabil-
ity. The reported sensitivity and specificity cutoffs, respectively,
ranged from 70 pg/mL (93% and 73%) to 1110 pg/mL (100% and
95%) for BNP and from 1203 pmol/L (100% and 91%) to 4000
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Management of Patent Ductus Arteriosus in Preterm Neonates
At a Glance
• Diagnosis and management of patent ductus arteriosus (PDA) in
preterm neonates is the most widely debated issue in modern
neonatology.
• Identifying hemodynamically significant PDA requires
comprehensive risk assessment tools, including host factors,
duct-related variables, parameters incorporating effects of the
duct on other organ systems, and echocardiographic markers.
• Indomethacin, ibuprofen, and acetaminophen are the most
widely used agents in various forms to close ductal patency;
however, the timing and method of administration to achieve
improvement in duct-related outcomes remain to be
investigated.
• Surgical ligation of a PDA is associated with adverse neonatal and
infantile outcomes; however, the issue of confounding by
indication is not resolved.
• Newer approaches of minimally invasive methods of ductal
ligation may confer benefit; however, further comparative
studies and the development of expertise are needed.
pmol/L (70% and 89%) for NTpBNP. Change in concentration on se-
rial measurements has been shown to correlate with changes in PDA
shunts, but the sensitivity remains weak.27 A significant overlap in
the range of BNP concentrations has been observed between neo-
nates with no PDA (0-118 pg/mL), small PDA (5-451 pg/mL), mod-
erate PDA (5-1270 pg/mL), and large PDA (33-4510 pg/mL).27 Simi-
larly, a significant overlap has been reported in NTpBNP
concentrations, limiting its clinical application. The reasons for such
variability remain unknown but may relate to the confounding ef-
fect of interatrial shunts and pulmonary hypertension.
Defining a Hemodynamically Significant PDA
Despite widespread use of the term, there is no consensus on the
definition of a hemodynamically significant PDA.28 Echocardio-
graphic criteria used in clinical trials vary from left heart dimen-
sions in 34 studies (the ratio of left atrium to aorta is the most com-
mon criterion [cutoff, 1.15-1.70]) to ductal diameter in 8 studies
(cutoff, 1.5-2.0 mm). Although PDA diameter exceeding 1.5 mm com-
bined with diastolic flow reversal in the descending aorta appears
to represent the best echocardiographic criterion, this only pro-
vides semiquantitative evidence of a high-volume shunt, and not its
clinical significance. The presence of a large PDA at 3 days of age was
associated with IVH (adjusted odds ratio, 4.2; 95% CI, 1.3-14.0) and
a composite of death or severe morbidity (adjusted odds ratio, 5.0;
95% CI, 1.4-19.0), but only for neonates of less than 28 weeks’
gestation.29 Neonates with a small PDA had outcomes similar to
those with no PDA.29 A PDA disease staging system that incorpo-
rates clinical condition and echocardiographic findings has been sug-
gested, but its clinical usefulness has not been evaluated.30 Further-
more, the proposed scoring systems do not account for host factors
such as gestational age or preexisting morbidities. Given the hetero-
geneity in previously conducted studies and the intense debate on
what constitutes a hemodynamically significant PDA, it is impor-
tant to develop and test a comprehensive disease staging system
that includes patient characteristics, clinical condition at assess-
ment, and markers of PDA shunt volume, as well as duration of ex-
posure to a PDA shunt.
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 Management of Patent Ductus Arteriosus in Preterm Neonates Review Clinical Review & Education

Table 1. Usefulness of Clinical Signs for Assessment of Patent Ductus Arteriosus (PDA) in Preterm Neonates2-7
Parameters Evaluated and
Source Methods Outcome
Evans and 41 Neonates with BW Parameters evaluated were BP
Moorcraft,4 <1500 g underwent daily and pulse pressure; outcome was
1992 echocardiography at hsPDA (widely patent PDA with
1-7 d of age LA:Ao ≥1.5) vs no hsPDA on
echocardiography
Skelton et al,7 55 Ventilated neonates Parameters evaluated were
1994 with BW <1500 g murmur, high pulse volume, and
underwent daily active precordium; outcome was
echocardiography and hsPDA on echocardiography
clinical examination at defined as PDA diameter ≥1.5
1-7 d of age mm plus left-to-right shunt plus
LA:Ao ≥1.4 (n = 10 at 1 and 2 d
of age and n = 9 at 3-5 d of age)
Davis et al,3 100 Neonates with BW Parameters evaluated were
1995 <1750 g studied at 3-7 d murmur, high pulse volume,
of age active precordium, CT ratio on
chest radiograph, and increased
vascular markings on chest
radiograph; outcome was PDA
with left-to-right shunt on
echocardiography (n = 23)
Alagarsamy 25 Neonates with GA <32 Parameters tested were HR >170
et al,2 2005 wk underwent clinical beats/min, grade 2 or higher
examination and murmur, active precordium,
echocardiography at 3 d systolic BP less than fifth
of age percentile, palpable dorsalis
pedis pulse, worsening
respiratory status; outcome was
hsPDA on echocardiography
defined as diameter >2 mm and
its ratio to descending aorta
>0.5 (n = 25 [12 with hsPDA,
2 with small PDA, and 11 with
no PDA])
Lubetzky et al,6 Comparison of BP before Parameters tested were systolic
2004 (at 8 h of age) and after and diastolic and mean BP and
(at 48 and 72 h of age) pulse pressure; cases were
successful indomethacin preterm neonates treated for
treatment initiated at respiratory distress syndrome
<24 h of age plus PDA on echocardiography at
<24 h of age (n = 32); no
controls
Han et al,5 Daily average BP 1 d Parameters tested were systolic
2011 before and ≤7 d after and diastolic BP and pulse
successful indomethacin pressure; cases were preterm
treatment neonates with hsPDA diagnosed
at <72 h of age that closed after
treatment (n = 72); controls
were neonates without hsPDA
Result
For BW <1000 g, hsPDA group had
lower average systolic and diastolic
and mean BP on each day; for BW
1000-1500 g, no difference in any
parameter between the 2 groups
At first 5 d of life: sensitivities were
0%, 30%, 44%, 67%, 78% for murmur;
50%, 70%, 78%, 78%, 78% for pulse
volume; 10%, 40%, 78%, 78%, 78%
for precordium; and specificities were
0%, 90%, 91%, 84%, 91% for murmur;
73%, 65%, 55%, 66%, 81% for pulse
volume; 70%, 73%, 61%, 66%, 76%
for precordium
Weighted κ value and
sensitivity/specificity:
0.41 and 42%/87% for murmur; 0.15
and 43%/74% for pulse volume; 0.32
and 26%/85% for precordium; 0.38
and 14%/95% for increased CT ratio
absolute; 0.29 and 8%/94% for
increased CT ratio relative; 0.24 and
27%/88% for increased vascular
markings; murmur combined with
pulse volume had highest positive
predictive value at 77%
Frequency of positive clinical signs
noted in neonates with hsPDA vs
neonates with no PDA: 1 vs 0 for
murmur, 1 vs 1 for precordium, 9 vs 8
for palpable dorsalis pedis, 8 vs 5 for
worsening respiratory status; hsPDA
group had higher HR and lower
systolic and mean BP but within
clinically normal range
All BPs increase after successful PDA
closure with indomethacin; no
difference in pulse pressure after vs
before PDA closure (mean [SD],
17 [7] vs 20 [12] mm Hg)
For GA <30 wk or BW <1500 g,
pretreatment systolic and diastolic
BP reduction in hsPDA group, Abbreviations: Ao, aorta; BP, blood
normalization by 3 d after initiation
of treatment with indomethacin, no pressure; BW, birth weight;
difference in pulse pressure between CT, cardiothoracic; GA, gestational
groups; for GA >30 wk or BW age; HR, heart rate; hsPDA,
>1500 g, no difference between hemodynamically significant patent
groups on any day ductus arteriosus; LA, left atrium.

conservative approach, which suggests that most PDAs close

Management
With regard to the management of PDA in preterm neonates, clini-
cians and researchers have yet to reach a consensus on which PDAs
to treat, when to treat, and how to treat. For the purpose of this re-
view, we assumed that a decision to treat has been made and evalu-
ated existing evidence for the management approaches available
(Figure 1). Some interventions have been tested in randomized clini-
cal trials (RCTs); however, a substantial proportion of evidence stems
from institutional experience or uncontrolled comparisons.
Conservative Management
Increasing concerns regarding surgical ligation and adverse
effects of pharmacological agents have resulted in adoption of a
by themselves. Some studies have combined fluid restriction,
diuretics, and increasing end-expiratory pressure in this
approach. Advantages include avoidance of pharmacological
adverse effects and surgery; however, disadvantages include vol-
ume overload to immature lungs and heart. 31 One study 32
reported increased risk of death or BPD in less aggressively
treated infants, but other researchers have shown beneficial
effects of a conservative approach when access to surgery is
an issue.33 Few well-designed studies have explored the natural
progression of PDA; however, it is difficult to conduct such stud-
ies given the association of PDA with morbidities. Despite con-
flicting evidence, the practice of conservative management is
increasing. In Canadian units over the last 8 years, the number of
neonates managed via a conservative approach has almost

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 Clinical Review & Education Review Management of Patent Ductus Arteriosus in Preterm Neonates

Table 2. Echocardiographic Indexes Used in Assessment of Left-to-Right Shunting Patent Ductus Arteriosus
(PDA) in Preterm Neonates and Suggested Cutoffs for Diagnosing Significant PDA
Effect of
Rising PDA
Parameter Variable Shunt Cutoffs
Direct Assessment of PDA
Size Absolute PDA diameter, mm ↑ Small is <1.5, moderate is ≥1.5
to <2, large is ≥2
Ratio of PDA to LPA diameter ↑ Small is <0.5, moderate is ≥0.5
to <1, large is ≥1
PDA diameter index to body weight, mm/kg ↑ ≥1.4
Flow pattern Ratio of end diastolic to peak systolic ↓ <0.5
velocity of shunt across PDA
Surrogate Measures of Shunt Volume
Excessive Ratio of left atrial diameter to aortic root ↑ ≥1.5
pulmonary blood measured using M-mode echocardiography
flow Ratio of left ventricular end diastolic ↑ ≥2.1
diameter to aortic root measured using
M-mode echocardiography
Ratio of early and late diastolic inflow ↑ >1
velocity across mitral valve
Left ventricle isovolumetric relaxation ↓ <35
time, ms
Left ventricular output, mL/min/kg ↑ >314
Mean LPA antegrade flow velocity, cm/s ↑ ≥42
End diastolic LPA antegrade velocity, cm/s ↑ ≥20
Reduced systemic Diastolic flow pattern in systemic arteries ↓ Small is antegrade diastolic flow,
blood flow (descending aorta, celiac, superior moderate is absent diastolic flow,
mesenteric, middle cerebral) large is retrograde diastolic flow
Abbreviations: LPA indicates left
Ratio of left ventricular output to superior ↑ ≥4 pulmonary artery; ↑, increasing; ↓,
vena cava flow decreasing.

doubled, while the use of surgical ligation has halved, with no
alteration in neonatal mortality or morbidity.34
Nonpharmacological Interventions
Suggested nonpharmacological interventions for PDA are
restricted fluid intake, increasing end-expiratory pressure, and
oxygen use, all of which need further evaluation. Restricted fluid
intake has been associated with a reduction in PDA and BPD but
has also been associated with reduced systemic blood flow.35,36 A
modest elevation of positive end-expiratory pressure can increase
pulmonary vascular resistance and thus reduce pulmonary blood
flow,37 which may be useful in reducing the shunt across a PDA.33
In the era of noninvasive respiratory management practices,
determination of optimal end-expiratory pressure via ongoing
assessment of hemodynamic status would be helpful. Oxygen is a
potent stimulator of postnatal ductal constriction. Noori et al38
reported a higher rate of PDA among neonates managed with a
lower saturation target (83%-89%) vs a higher target (89%-
94%). However, a recent meta-analysis39 of oxygen saturation tar-
gets reported no difference in PDAs requiring therapy (relative risk
[RR], 1.01; 95% CI, 0.95-1.08).
Pharmacological Interventions
Pharmacological interventions for PDA include those that treat the
symptoms (eg, heart failure) and those that stimulate PDA closure.
Symptomatic treatments include diuretics (eg, furosemide and di-
goxin). However, 3 RCTs of furosemide showed no apparent
benefit,40 and digoxin is used infrequently,41 with no robust clini-
cal studies of its effects. Pharmacotherapy for PDA closure is based
on the role of prostaglandin in ductal constriction. The biochemical
mechanisms include effects on cyclooxygenase and peroxidase en-
zymes. Indomethacin, the most widely used agent, is more preva-
lent in North America, and ibuprofen is more commonly used in
Europe and Asia.42 Studies of the use of acetaminophen are also
surfacing.
Indomethacin
By inhibiting prostaglandin E2, indomethacin promotes ductal
closure.43 Rates of closure following an initial course vary from 48%
to 98.5% depending on the dose, duration, and method of
administration43-45 and from 40% to 50% with a second course.45
Exposure to more than 2 courses of indomethacin has been asso-
ciated with periventricular leukomalacia; however, the cause-and-
effect relationship has not been established.46 The likelihood of ef-
fectiveness of indomethacin decreases with decreasing gestational
age and with increasing postnatal age.47 Adverse effects include re-
nal dysfunction, gut ischemia, and impaired platelet aggregation.
Several approaches have been attempted to fine-tune indometha-
cin treatment, including prophylaxis and therapeutic use with vari-
ous dosing strategies. As prophylaxis, indomethacin is adminis-
tered in the first 12 hours after birth. The aim is to reduce the effect
of PDA on hemodynamic instability and thus reduce the severity of
IVH. A review of 19 studies identified a reduction in symptomatic PDA
and the need for surgical ligation with prophylactic indomethacin48;
however, lack of improvement in long-term outcomes, despite a re-
duction in the severity of IVH, has created diverse opinion and prac-
tices regarding prophylactic indomethacin.
For therapeutic use, 3 RCTs indicated a reduction in sympto-
matic PDA (RR, 0.36; 95% CI, 0.19-0.68) and in duration of oxygen
therapy following indomethacin use in the early asymptomatic phase;

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 Management of Patent Ductus Arteriosus in Preterm Neonates Review Clinical Review & Education

Table 3. Studies Evaluating the Ability of Various Echocardiography Indexes to Describe a Hemodynamically
Significant Patent Ductus Arteriosus (hsPDA) in Preterm Neonates1,8,12,13,15-20
Population and
Source Methods Indexes Tested Outcome Main Results
Johnson et BW <1750 g; LA:Ao, LV:Ao, Clinical diagnosis LA:Ao >1.4 associated with least
al,15 1983 M-mode fractional of hsPDA misclassification rate (17%); only
echocardiography shortening, LV 5% non-PDA neonates had LA:Ao >1.5
after admission preejection period:
(415 with PDA and LV ejection time
1496 controls)
Walther et BW <1250 g; serial LVO Clinical diagnosis LVO in neonates with hsPDA ≥314
al,16 1989 Doppler of hsPDA mL/min/kg vs range of 190-310
echocardiography mL/min/kg in neonates without
daily for first 10 d hsPDA
(14 with PDA and
11 controls)
Evans and BW <1500 g; 151 PDA diameter, RVSV:LVSV When ASD was small or absent:
Iyer,19 1994 echocardiography LA:Ao, LVSV, LVO, (inversely related RVSV:LVSV correlates with LA:Ao
with PDA in 39 DADF pattern to PBF) (r = 0.45), LVSV (r = 0.38), LVO
neonates (69 had (r = 0.43), and PDA diameter
absent or small (r = 0.8); ASD >2 mm negatively
[<2 mm] ASD) affected all correlations except PDA
diameter and DADF pattern; PBF
directly related to DADF pattern
(retrograde > absent > antegrade)
Iyer and BW <1500 g; 463 LA:Ao hsPDA defined as LA:Ao ≥1.5 after day 1 (sensitivity
Evans,13 echocardiography diameter ≥1.5 mm 88% and specificity 95%); PDA
1994 in 56 neonates >1.5 mm (DADF absent or retrograde
(180 with PDA and in 94%); PDA <1.5 mm (DADF absent
283 controls) in 9% and none retrograde)
Evans and BW <1500 g; 465 PDA diameter DADF on Doppler For no PDA, 162 antegrade, 1 absent,
Iyer,12 1995 echocardiography <1.5 mm (n = 61), echocardiography: 0 retrograde; for PDA <1.5 mm, 58
in 51 neonates 15-1.7 mm antegrade, absent, antegrade, 3 absent, 0 retrograde; for
(178 with PDA and (n = 23), >1.7 mm retrograde PDA 1.5-1.7 mm, 11 antegrade,
163 controls) (n = 58), >2.1 mm 8 absent, 4 retrograde; for PDA >1.7
(n = 36) mm, 1 antegrade, 7 absent, 50
retrograde; for PDA >2.1 mm, 0
antegrade, 0 absent, 36 retrograde
El Hajjar et GA <30 wk; LA:Ao, PDA LVO:SVC ≥4 as Sensitivity/specificity/correlation
al,8 2005 echocardiography diameter, mLPAv, calculated from coefficient (r2): for LA:Ao ≥1.4 is
at <48 h of age EDLPAv echocardiography 92%/91%/0.57; for PDA ≥1.4 mm/kg
(19 with PDA and is 94%/90%/0.57; for mLPAv ≥42
14 controls) cm/s is 91%/92%/0.30; for EDLPAv
≥20 cm/s is 92%/100%/0.35
El-Khuffash BW <1500 g; serial CAF:LVO hsPDA defined as At 1 d of age, no difference between
et al,18 2008 echocardiography diameter >1.4 mm groups; at 3 d of age, hsPDA
at 1 and 3 d of age plus LA:Ao >1.5 associated with low (median [range])
(19 with PDA and CAF:LVO (0.21 [0.05-0.42]) vs 0.07
14 controls) [0.02-0.26]); CAF:LVO correlated
with PDA diameter (r = 0.71) and
LA:Ao (r = 0.6)
Groves et al,1 GA <31 wk; serial PDA diameter, SVC Low DA flow, high Retrograde DADF more closely
2008 echocardiography flow, retrograde LVO as calculated associated with high LVO and lower
Abbreviations: Ao, aorta; ASD, atrial
at 5, 12, 24, and 48 DADF from DA flow than PDA diameter alone;
h of age in 80 echocardiography incidence of retrograde DADF when septal defect; BW, birth weight;
neonates PDA diameter exceeds the median was CAF, celiac artery flow; DA,
34% and 46% at 5 and 48 h of age, descending aorta; DADF, descending
respectively aorta diastolic flow; EDLPAv, end
Broadhouse 75 Stable preterm Echocardiography PSV calculated PSV correlated with retrograde DADF diastolic left pulmonary artery
et al,17 2013 infants had markers: PDA from MRI (r2 = 0.84), PDA diameter (r2 = 0.63), velocity; ED/max, end diastolic
echocardiography diameter ≥1.5 mm, LA:Ao (r2 = 0.59), and ED/max
velocity to peak systolic velocity ratio
and cardiac MRI LA:Ao >1.4, (r2 = 0.55); increased PSV associated
within 10 h of each retrograde DADF, with decreasing lower and upper body of patent ductus arteriosus shunt;
other (15 with PDA ED/max <0.5 flows but majority at least −2 SD of GA, gestational age; LA, left atrium;
and 60 controls) controls; for PDA with retrograde LPA, left pulmonary artery diameter;
DADF, PSV range 169-435 mL/min/kg; LV, left ventricle; LVO, left ventricular
for PDA without retrograde DADF,
output; LVSV, left ventricular stroke
PSV range 18-86 mL/min/kg
output; mLPAv, mean left pulmonary
Sehgal and GA <32 wk; LA:Ao >1.5, PDA diameter Sensitivity/specificity/correlation artery velocity; MRI, magnetic
Menahem,20 retrospective LVO:SVC ≥4, >3 mm coefficient (r2): LA:Ao >1.5 is
2013 review of PDA:LPA ≥1, 100%/6%/0.76; LVO:SVC ≥4 is resonance imaging; PBF, pulmonary
pretreatment EDLPAv >30 cm/s, 95%/83%/0.67; PDA:LPA ≥1 is blood flow; PSV, PDA shunt volume;
echocardiography PDA Vmax <1.5 m/s 100%/61%/0.67; EDLPAv >30 cm/s RVSV, right ventricular stroke output;
of neonates with is 95%/72%/0.67; PDA Vmax SVC, superior vena cava flow; Vmax,
PDA (52 with PDA) <1.5 m/s is 95%/46%/0.68 maximum velocity.

however, there was no difference in any other neonatal outcomes, nificant reduction in pulmonary hemorrhage and in need for later
and long-term neurodevelopmental outcomes were not studied.49 medical treatment.50 In the early symptomatic phase, an RCT indi-
With early asymptomatic treatment, a recent RCT reported a sig- cated that indomethacin was 2.3 times more effective in PDA clo-

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 Clinical Review & Education Review Management of Patent Ductus Arteriosus in Preterm Neonates

Table 4. Investigations Into Early Echocardiography Prediction of Hemodynamically Significant Patent Ductus
Arteriosus (hsPDA) in Preterm Neonates9-11,21,22

Source Methods Outcome Tested Sensitivity/Specificity

Kluckow and 116 Neonates with BW
Evans,21 1995 <1500 g had early
echocardiography at <31 h
of age; 42 developed hsPDA
at ≥5 d of age
Su et al,11 68 Neonates with BW
1997 <1500 g and on mechanical
ventilation had daily Doppler
echocardiography from 1-7 d
of age to document PDA
shunt pattern
Ramos et al,10 115 Neonates with BW
2010 <1000 g had early
echocardiography at ≤4 d of
age; 59% subsequently
treated for hsPDA
Harling et al,9 45 Neonates with GA <32 wk
2011 had serial echocardiography
at 24 and 72 h of age; 28 had
PDA on first scan, 22 on
second scan; 12
subsequently treated for
hsPDA
Thankavel et 96 Neonates with GA ≤30 wk
al,22 2013 had echocardiography at
3 (early) and 10 (late) d
of life
hsPDA defined as by clinical
signs or symptoms plus
echocardiography criteria
(PDA diameter ≥1.5 mm
plus absent or retrograde
DADF)
hsPDA defined as presence
of ≥2 clinical or radiological
signs plus left-to-right
shunt PDA on
echocardiography
Need for subsequent
treatment for hsPDA as
determined by clinicians
based on clinical signs plus
echocardiography showing
large PDA
Need for subsequent
treatment for hsPDA as
determined by clinicians
based on clinical features
plus echocardiography
showing large PDA
Spontaneous PDA closure
on late echocardiography
without PDA-specific
treatment
LA:Ao ≥1.5 (29%/91%); left ventricular
output ≥300 mL/min/kg (26%/92%);
absent or retrograde DADF (68%/85%);
PDA diameter ≥1.5 mm (81%/85%)
First growing pattern (64%/81%); first
pulsatile pattern (93%/100%)
PDA:LPA ≥0.5 (78%/80%)
Presented separately for scans at 24
and 72 h; PDA diameter ≥2 mm/kg
(91%/59% and 89%/70%); pulsatile PDA
flow pattern (91%/59% and 67%/78%);
LA:Ao ≥1.4 (70%/29% and 56%/50%);
green pixels on color Doppler ≥50%
(64%/47% and 70%/44%)
Presented separately for neonates at
GA ≥27 and >27 wk; PDA:LPA
≥0.5 (92%/55% and 87%/89%); PDA
diameter ≥1.5 mm (75%/78% and Abbreviations: Ao, aorta; BW, birth
74%/94%); LA:Ao ≥1.4 (89%/72% and weight; DADF, descending aorta
67%/86%); ratio of early to late diastolic diastolic flow; GA, gestational age;
flow velocity across mitral valve LA, left atrium; LPA, left pulmonary
>1 (100%/6% and 93%/13%) artery.

Figure 1. Therapeutic Modalities for the Management of Patent Ductus Arteriosus (PDA)

Hemodynamically significant PDA

Watchful Nonpharmacological Pharmacological Mechanical

observation approaches approaches approaches

Fluid restriction, Agents to Agents to close Surgical Transcatheter Videoscopic

increase reduce ductal patency ligation ligation ligation
end expiratory effect of PDA,
pressure, diuretics,
oxygen digoxin

Indomethacin Ibuprofen Acetaminophen

Oral IV Oral IV Oral IV

IV indicates intravenous.

sure than placebo, and when used as a backup to nonpharmaco-
logical management results in similar rates of closure.44 Two other
studies, one RCT and one before-and-after study,51,52 evaluated early
vs late symptomatic treatment and reported that delay in treat-
ment can be tolerated and may reduce exposure to pharmacologi-
cal agents; however, there was an increase in the combined out-
come of death or BPD.52 Conversely, one RCT comparing the use of
early (day 3) vs late (day 7) indomethacin use indicated that early
treatment was associated with higher rates of PDA closure but also
with higher rates of renal adverse effects and no benefit in respira-
tory outcomes.53
Indomethacin has been used orally, rectally, intravenously, and
intra-arterially. Six studies of oral use (in 9-74 neonates) have re-
ported closure rates between 67% and 70%.43 Oral use (in 5 neo-
nates) and rectal use (in 26 neonates) has been reported to be suc-
cessful in 76% of cases.43 Intravenous indomethacin has been used

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 Management of Patent Ductus Arteriosus in Preterm Neonates
Figure 2. Reported Comparison of Various Patent Ductus Arteriosus Treatment Approaches
IV Indomethacin
Placebo
Ligation Oral indomethacin Oral ibuprofen
Prophylactic vs selective
in several investigations; however, the dose and duration of treat-
ment varied.43 Various dosing strategies have also been used. Most
studies used 3 doses of 0.1 to 0.2 mg/kg per dose. One study54 used
escalating doses, starting with 0.2 mg/kg and increasing to 1 mg/kg
in nonresponders, with 98.5% success; however, concerns regard-
ing adverse effects with higher and frequent doses have not been
addressed. A further study55 compared high-dose (0.2-0.5 mg/kg
per dose) vs low-dose (0.1 mg/kg per dose) indomethacin after de-
tecting persistence of PDA following the conventional 3 doses and
reported similar efficacy in PDA closure (55% vs 48%, respec-
tively). However, high-dose indomethacin use was associated with
renal compromise and with moderate to severe retinopathy.
The usual duration of a course of indomethacin is 48 to 72 hours.
Although ductal closure is a lengthy remodeling process, 5 RCTs re-
vealed no difference in PDA closure rates but an increased rate of
NEC associated with prolonged indomethacin use (RR, 1.87; 95% CI,
1.07-3.27)56; therefore, a prolonged course is not recommended. In-
domethacin also affects cerebral, renal, and splanchnic blood flow.
Studies have reported a reduction in blood flow,57 a higher closure
rate (81% vs 43%, P = .03),58 and no difference in closure rate59 as-
sociated with bolus infusion compared with continuous infusion. A
systematic review concluded that evidence is limited to draw any
conclusion on the superiority of either approach.60
Ibuprofen
Available in 2 preparations, ibuprofen lysine and ibuprofen–tris
(hydroxymethyl)aminomethane, ibuprofen is a nonselective cy-
clooxygenase inhibitor that does not alter cerebral, renal, or gut per-
fusion. It can be given orally, which increases the acceptability in
certain settings. Several studies have confirmed that ibuprofen has
potency for PDA closure similar to that of indomethacin and a low
adverse effect profile. Major adverse effects are oliguria, high bili-
rubin levels, and gastrointestinal hemorrhage, and the use of ibu-
profen–tris(hydroxymethyl)aminomethane has been associated with
higher rates of gastrointestinal complications.61 The usual dose is 10
mg/kg on day 1, followed by 2 doses of 5 mg/kg 24 hours apart.
The use of intravenous or oral ibuprofen prophylactically has
been shown to reduce the incidence of PDA on day 3 after birth
(RR, 0.34; 95% CI, 0.16-0.73 for oral delivery and RR, 0.37; 95%
CI, 0.29-0.47 for intravenous delivery) compared with placebo or
no treatment but has demonstrated no benefit on any other neo-
natal outcomes.62 The use of oral ibuprofen was associated with
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Review Clinical Review & Education
Low vs high dose
Short vs long course
Bolus vs infusion
Escalating vs fixed dose
IV Ibuprofen
Low vs high dose
Bolus vs infusion
Early vs expectant
Oral acetaminophen
IV indicates intravenous.
higher rates of gastrointestinal hemorrhage. A detailed systematic
review of studies that used ibuprofen therapeutically indicated
that compared with placebo oral ibuprofen reduced PDA (RR,
0.26; 95% CI, 0.11-0.62) and intravenous ibuprofen reduced the
need for rescue treatment (RR, 0.58; 95% CI, 0.38-0.89).63 In the
same study, a comparison of oral vs intravenous ibuprofen
reported higher rates of closure with oral ibuprofen (RR, 0.37,
95% CI, 0.23-0.61). Higher closure rates were also reported with
high-dose compared with low-dose ibuprofen (RR, 0.38; 95% CI.
0.15-0.96). Early use of ibuprofen vs its use when PDA became sig-
nificant resulted in a reduction in oxygen use of 2 days in the first
28 days after birth. A further study64 compared bolus with con-
tinuous infusion of ibuprofen and reported a higher rate of sus-
tained closure after continuous infusion (68% vs 86%, P = .03).
However, no other neonatal outcomes were affected in any of
these studies. As such, although ibuprofen is an effective treat-
ment for PDA in both oral and intravenous forms, the effect of
early treatment of PDA with ibuprofen on other neonatal out-
comes and neurodevelopmental outcomes is unknown to date.
Acetaminophen
Acetaminophen is suspected to act on PDA via peroxidase-
mediated inhibition of conversion of prostaglandin G2 to prosta-
glandin H2. The compound’s pharmacokinetic data or route and dose
of administration have not been well studied. Adverse effects in-
clude hepatotoxicity and the effect on hemodynamics and thermo-
dynamics. Most case reports have evaluated acetaminophen use af-
ter failure of PDA closure by routine measures, and no studies to date
have compared it with placebo. Some studies65,66 report the use of
15 mg/kg per dose every 6 hours for 2 to 7 days; however, effects
on neonatal and neurodevelopmental outcomes are not well known.
The requirement for prolonged administration calls into question the
efficacy of acetaminophen because PDA closure may be related to
time rather than drug administration.
Comparison of Pharmacological Agents
All 3 agents have been tested against one another in various com-
binations (Figure 2), with no differences observed among them in
the rate of PDA closure or failure of PDA closure, any other neona-
tal outcomes, or adverse effects. This includes 7 RCTs testing oral
indomethacin vs oral ibuprofen (RR, 0.82; 95% CI, 0.52-1.29),63 12
studies of intravenous indomethacin vs intravenous ibuprofen (RR,
(Reprinted) JAMA Pediatrics Published online July 13, 2015 E7
 Clinical Review & Education Review Management of Patent Ductus Arteriosus in Preterm Neonates

1.03; 95% CI, 0.74-1.43),63 3 small studies of intravenous indometha-
cin vs oral ibuprofen (RR, 0.94; 95% CI, 0.56-1.60),67 and 2 RCTs of
oral acetaminophen vs oral ibuprofen (RR, 0.83; 95% CI, 0.60-1.15
in one study68 and RR, 1.22; 95% CI, 0.57-2.62 in the other study69).
Mechanical Approaches
Surgical Ligation
Due to concerns about pneumothorax, chylothorax, vocal cord palsy,
postligation left ventricular dysfunction, BPD, retinopathy, and ad-
verse neurodevelopmental outcomes following surgery, surgical li-
gation of PDA is only undertaken in patients when medical treat-
ment has failed and if the patient requires extensive respiratory
support or is unable to be weaned off a ventilator. However, it is dif-
ficult to differentiate whether these complications are due to the sur-
gical procedure, actions associated with surgery (eg, need for me-
chanical ventilation, analgesia, anesthesia, and handling of the left
lung and pleura), systemic inflammatory response, or prolonged ex-
posure to a hemodynamically significant PDA.
Evaluations of surgical vs pharmacological ligation have used a
variety of methods and produced inconsistent results. In studies from
the 1970s to 1980s (the presurfactant and preantenatal corticoste-
roid era), prophylactic surgical ligation of PDA was reported to be
associated with shorter duration of mechanical ventilation, re-
duced medical therapy, and less time to achieve full feeds,70 while
surgical ligation after failure of basic medical therapy was shown to
have no additional benefit.71 Another study44 from the same era ran-
domized preterm neonates first to indomethacin vs placebo, and
subsequently symptomatic patients in the placebo group were ran-
domized to early surgical ligation vs a course of indomethacin and
then surgical ligation in refractory cases. Pneumothorax rates were
higher in the surgery group, but there was no difference in BPD or
duration of respiratory support.44 Notably, 67% of neonates ran-
domized to receive indomethacin (followed by ligation if needed)
did not require ligation. A more recent study72 reported that delay-
ing ligation in neonates with significant PDA reduced the need for
ligation, without increasing significant morbidity. However, a com-
parison of early ligation vs delayed ligation in retrospective studies
has generated contrasting results.73,74
Recently, surgical ligation has come under scrutiny because sev-
eral studies and a systematic review identified it to be associated with
higher morbidity and with lower mortality. The possibility of sur-
vival bias and confounding by indication75,76 has been raised, and
there is a need for conducting large-scale randomized studies or iden-
tifying the severity-of-illness scores related to PDA to compare the
effect of surgery.
Novel Approaches to Mechanical Ligation
The noninvasive method of video-assisted thoracoscopic surgery has
been attempted in preterm neonates.77,78 Complications include air
leak, effusion, and the need to convert to open surgery in the case of
significant hemodynamic instability.78 Transcatheter ligation is a treat-
ment of choice in term neonates; however, its use in preterm neo-
nates is still evolving. Two studies79,80 (with 8 and 6 neonates each)
reported successful experiences with transcatheter ligation of PDA.
Neither study reported any procedure-related complications.
Conclusions and Implications for Practice
and Research
Diagnosis of PDA, especially significant PDA, remains a challenge.
Although echocardiographic characteristics have been identified,
they are not reliable enough to effectively identify a clinically sig-
nificant PDA in which treatment can lead to improved long-term out-
comes. Diastolic flow reversal in the descending aorta remains the
best clinical marker of a high-volume shunt across a PDA. However,
even in an infant in whom this perturbation of blood flow to other
organs has been identified, the choice and timing of treatment are
still uncertain. Increasingly, more neonates are managed conserva-
tively, and the number of infants receiving surgical ligation is declin-
ing; however, the effect of this approach on long-term cardiovas-
cular, pulmonary, and neurodevelopmental health is unknown to
date. Indomethacin and ibuprofen remain the mainstays of medi-
cal management, whereas acetaminophen use is emerging as a less
toxic option. Surgical ligation is offered mostly as a last resort; how-
ever, newer modalities such as transcatheter and videofluoro-
scopic ligation may offer better alternatives, but experience with
these techniques is limited.
Further studies are needed for both diagnosis and treatment that
take into account modern practices, including antenatal corticoste-
roid use, minimally invasive respiratory support, and minimal oxy-
gen on day 2 or 3 after birth. For diagnosis, comprehensive risk as-
sessment tools are needed that include patient characteristics, duct-
related variables, parameters incorporating effects of the duct on
other organ systems, and echocardiographic markers at the time of
decision making. From a treatment perspective, multicenter ran-
domized studies are required to evaluate the benefits and risks of
strategies such as (1) no treatment, (2) prophylactic, early asymp-
tomatic, or symptomatic treatment, and (3) different agents with
long-term cardiovascular, respiratory, and neurodevelopmental
health outcomes.

ARTICLE INFORMATION Administrative, technical, or material support: Jain. manuscript; and decision to submit the manuscript
Accepted for Publication: April 6, 2015. Study supervision: Shah. for publication.

Published Online: July 13, 2015.
doi:10.1001/jamapediatrics.2015.0987.
Author Contributions: Dr Shah had full access to all
the data in the study and takes responsibility for the
integrity of the data and the accuracy of the data
analysis.
Study concept and design: Shah.
Acquisition, analysis, or interpretation of data: Jain.
Drafting of the manuscript: All authors.
Critical revision of the manuscript for important
intellectual content: Shah.
Conflict of Interest Disclosures: None reported.
Funding/Support: Dr Shah is supported by an
Applied Research Chair in Reproductive and Child
Health Services Research from the Canadian
Institutes of Health Research.
Role of the Funder/Sponsor: The Canadian
Institutes of Health Research had no role in the
design and conduct of the study; collection,
management, analysis, and interpretation of the
data; preparation, review, or approval of the
Additional Contributions: Ruth Warre, PhD
(Maternal–Infant Care Research Centre at Mount
Sinai Hospital) critically reviewed the manuscript.
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