Diagnosis of the Preterm Patent Ductus

Arteriosus: Clinical Signs, Biomarkers, or Ultrasound?

Nick Evans, DM, MRCPCH
The current uncertainty in relation to treatment of the preterm patent ductus arteriosus
reects limitations to our understanding of the pathophysiology of ductal shunting, most
particularly which ducts matter to which babies and when they matter. Doppler ultrasound
offers a pragmatic tool with which to assess ductal patency and shunt signicance and to
allow prediction of spontaneous and therapeutic closure. Biomarkers, such as B-type
natriuretic peptide, and clinical signs may have a diagnostic role where ultrasound is not
available and also possibly as an adjunct to echocardiography in determining the patho-
physiological impact of a ductal shunt in an individual baby.
Semin Perinatol 36:114-122 2012 Elsevier Inc. All rights reserved.
KEYWORDS ductus arteriosus, echocardiography, ibuprofen, indomethacin, infant premature,
systemic blood ow
T
he preterm persistent ductus arteriosus (PDA) has
swung from being viewed as the cause of most adverse
outcomes in preterm neonatology
1-3
to being proposed as
an innocent physiological bystander.
4-6
Much of the con-
troversy around the preterm PDA has centered on when
and how to treat, but there is a more fundamental contro-
versy than this, which is how we diagnose the problem as
pathological in the rst place. Delve a little deeper into the
clinical trials that make up the systematic reviews that
have stirred the current controversy, and youll nd trials
whose denitions of a signicant PDA are as varied as the
vintage of the trials themselves.
4-6
Early trials often used
just clinical signs; ultrasound then began to be used more
frequently, but usually, initially, only for dening a ductus
as open or closed. More recently, there has been recogni-
tion that the ductus arteriosus is not a dichotomous vari-
able, and echocardiographic markers of hemodynamic sig-
nicance have started to be used. Even then, there is little
or no standardization of what makes up the apocryphal
hemodynamically signicant PDA.
7
In this article, I will reviewthe evidence around the 3 main
modalities that have been used for PDA diagnosis, focusing
initially on ultrasound, as that is still the gold standard, but
also reviewing the accuracy of clinical signs and then expand-
ing that into the relatively recently explored areas of blood
biomarkers of PDA, specically focusing on B-type natri-
uretic peptide (BNP).
Doppler Ultrasound
and the Ductus Arteriosus
Doppler ultrasound provides accurate information on
ductal patency and can give us some information in an
individual baby of the size of a ductal shunt and the clin-
ical impact of that shunt. Doppler ultrasound allows the
direct imaging of the ductus to determine patency and
degree of constriction. This is aided by color Doppler
mapping that conrms the presence and direction of any
shunt and the degree of constriction. Pulsed Doppler can
be used to more accurately measure the pattern and veloc-
ity of the shunt as well as assessing disturbance to the
pattern of diastolic blood ow in the major vessels on
either side of the duct. So, Doppler ultrasound assessment
of the ductus can answer several questions: Is the ductus
patent? If the ductus is patent, how wide is it or, in other
words, how well has it constricted? What is the direction
and velocity of the shunt? What is the signicance of the
shunt and what is the impact on the systemic and pulmo-
nary circulation? Finally, is this babys ductus going to
close spontaneously? Dealing with these in turn:
Department of Newborn Care, Royal Prince Alfred Hospital, University of
Sydney, Sydney, New South Wales, Australia.
Address reprint requests to Nick Evans, DM, MRCPCH, Department of
Newborn Care, Royal Prince Alfred Hospital, Missenden Rd, Camper-
down, Sydney, New South Wales 2111, Australia. E-mail: nevans@med.
usyd.edu.au
114 0146-0005/12/$-see front matter 2012 Elsevier Inc. All rights reserved.
doi:10.1053/j.semperi.2011.09.021
Is the Ductus
Arteriosus Patent?
The resolution of modern ultrasound is such that indirect
echocardiographic methods for assessing ductal patency
have been rendered largely obsolete, though as described
below, they may add information on the signicance of a
ductal shunt. Determining patency should involve direct im-
aging of the duct. The ductus leaves the main pulmonary
artery (MPA) at its junction with the left pulmonary artery
(LPA) and continues in the same posterior direction as the
MPA to describe an arch into the descending aorta (Fig. 1).
Imaging involves placing the transducer over the ductus in a
high parasternal position just to the left of the midline and
aligning the beam in a true sagittal plane. The user should
initially align the beam down the body of the MPA and then
angle slightly to the left to image the root of the LPA (seen as
a diverticulum); the course of the ductus will be seen just
superior to the root of the LPA (Fig. 2).
The widely patent duct is readily apparent on 2-dimen-
sional (2D) imaging, but conrmation of patency requires
color Doppler to show the shunt of blood through the duct
(Fig. 3). The common left-to-right direction of blood ow
(traveling toward the transducer) produces a red signal and
contrasts strongly with the streams away fromthe transducer
in the LPA and descending aorta, which appear blue. The
uncommon mainly right-to-left ductal shunt is easy to miss
because it produces a blue signal like that produced by the
adjacent streams.
How Well Has the
Ductus Arteriosus Constricted?
The fetal ductus arteriosus is a large vessel, not much
smaller than the MPA, reecting the fact that it carries
90-95% of the cardiac output. In the early postnatal pe-
riod, almost all babies will show some degree of constric-
tion from this fetal size. In healthy term babies, this con-
striction is universal and powerful.
8
In preterm babies it is
more variable.
9
These differences in ductal constriction are
readily apparent on color Doppler and 2D imaging, (Fig.
3). Measurement of the degree of constriction is often
expressed as the diameter at the site of maximum constric-
tion, which is usually at the pulmonary end. With high-
resolution equipment, this can be measured just using 2D
imaging. However, the course of the duct is not ideal for
edge resolution; so, ductal diameter or width is often mea-
sured using the color Doppler stream.
10
What Are the Direction and
Velocity of the Ductal Shunt?
The direction and velocity of the shunt through the patent
duct are direct products of the relative pressures at each end
Figure 1 (A) shows the position and orientation of the transducer. (B) shows the anatomical relationships of the ductus
from above demonstrating how the ductus is a slightly left-sided continuation of the main pulmonary artery. The
ductus describes an arch into the descending aorta as seen from the left side in (C). Image by courtesy of Springer,
Heidelberg. (Color version of gure is available online.)
Figure 2 The true sagittal ductal cut with a widely patent duct ap-
parent on 2-dimensional imaging (A) and on color Doppler (B) with
the red left-to-right ductal shunt contrasting with the blue streams
in the left pulmonary artery and descending aorta. Image by cour-
tesy of Springer, Heidelberg. (Color version of gure is available
online.)
Diagnosis of the preterm patent ductus arteriosus 115
of the duct. These waves are not synchronous, with the pres-
sure wave from the right heart arriving at the duct slightly
earlier than the left, mainly owing to closer proximity to the
heart. When the pulmonary pressures are clearly lower than
systemic or clearly higher, the shunt will be left-to-right or
right-to-left, respectively. However, as the pulmonary pres-
sures approach systemic, there will be some right-to-left
shunting in early systole followed by left-to-right shunting.
This bidirectional pattern occurs before pulmonary pressures
exceed systemic. As pulmonary pressures rise further, the
velocity and duration of the right-to-left shunt will increase
(Fig. 4).
What Is the
Volume of the Ductal Shunt?
Doppler ultrasound assessments of volume of ductal shunt
are divided into direct and indirect assessments of this ow
volume. The direct assessments are derived from the laws of
uid dynamics, which dictate that ow must be the product
of the size (or cross-sectional area) of the vessel and the
pressure gradient across that vessel. The size can be estimated
as described above from direct 2D imaging together with
color Doppler, and the pressure gradient can be estimated
from the Doppler velocities. Direct ow calculation as used
Figure 3 Varying degrees of ductal constriction as seen with color Doppler, from (A) where the duct is closed with no
shunt apparent to (B) where the duct is well constricted with a thin shunt streamto (C) where the duct is widely patent.
Image by courtesy of Springer, Heidelberg. (Color version of gure is available online.)
Figure 4 The range of ductal shunt pattern from pulsatile left-to-right (A) to bidirectional (B) to predominantly right to
left (C). Image by courtesy of Springer, Heidelberg. (Color version of gure is available online.)
116 N. Evans
for ventricular outputs is rarely used, as important assump-
tions may not be true; rstly, one cannot assume that the
orice is round; hence, the relationship between diameter
and cross-sectional area will not hold. Secondly, the Doppler
owmeasurements assume laminar owwhere ductal owis
usually turbulent. So, although we would use the important
components of a ow calculation (diameter and ow veloc-
ity) to build up the picture of signicance, we usually would
not combine them as a calculation of ow volume.
The indirect assessments reect the impact of a left-to-
right shunt on cardiac chamber dilatation and on Doppler
owpatterns on either side of the duct. Blood shunting left to
right through the duct will bypass the right heart, directly
entering the main pulmonary artery to increase pulmonary
blood ow (PBF) and so increase the volume load on the left
heart. The result is an increase in left atrial size, expressed as
the left atrial to aortic root ratio (LA:Ao), increase in left
ventricular size, usually measured by end-diastolic diameter
and increase in left ventricular output (Fig. 5).
The other slightly less indirect consequence of a left-to-
right ductal shunt is the disturbance to ow pattern in the
major vessels on either side of the duct. Blood shunts through
the ductus throughout the cardiac cycle, but in both circula-
tions, there is the least blood moving in diastole; so, more
disturbance in both arterial ow patterns is seen in diastole
than in systole. With increasing ductal shunt size, the normal
low-velocity antegrade diastolic ow in the postductal de-
scending aorta becomes progressively absent and then retro-
grade (Fig. 6A). The corollary to this on the other side of the
shunt is that the normal low-velocity diastolic owin the LPA
increases in antegrade velocity; indeed, all measures of LPA
velocity will increase, including mean velocity (Fig. 6B).
The validation of any of these measures runs into the prob-
lem of what should be the gold standard. Convention in
cardiology is that size of left-to-right shunts is expressed as a
ratio of the PBF (Qp) to the systemic blood ow (SBF) (Qs),
usually written as Qp:Qs. In the paradigm of an isolated
ductal shunt, Qp is represented by the left ventricular output,
whereas Qs is represented by the right ventricular output. As
we can measure both of these in the newborn, we should be
able to measure Qp:Qs, but this is confounded by the com-
mon coexistence of a left-to-right foramen ovale shunt. These
shunts are variable but can be quite large. We explored the
validation of the above direct and indirect measures by mea-
suring Qp:Qs in a cohort of pretermbabies (1500 g) with a
Figure 5 The measurement of the left atrial to aortic root ratio with
m-mode. The green line shows the path of the m-mode beamon the
2-dimensional image. This left atrial to aortic root ratio measured
1.94 and is raised. Image by courtesy of Springer, Heidelberg.
(Color version of gure is available online.)
Figure 6 The disturbance of ow on either side of a large ductus in (A), the left pulmonary artery showing the
measurement of peak diastolic velocity and mean velocity. (B) The retrograde diastolic ow in the descending aorta.
Image by courtesy of Springer, Heidelberg. (Color version of gure is available online.)
Diagnosis of the preterm patent ductus arteriosus 117
PDA and a small atrial shunt during the rst week of life.
10
In
this study, Qp:Qs was signicantly correlated with PDAcolor
Doppler diameter, LA:Ao, left ventricular (LV) stroke vol-
ume, and LV output. However, diameter had the closest cor-
relation (r 0.8) compared with LA:Ao (r 0.45), LVstroke
volume (r 0.38), or LV output (r 0.43). A diameter 2
mm was usually associated with a Qp:Qs 1.7:1. The veloc-
ity of the left-to-right shunt did not add to these predictive
relationships, but these studies were done in the rst week
when shunt velocities fall into a narrow range, usually 2
m/s. After the rst week, it is likely that shunt velocity will be
a more important determinant of shunt size as velocities will
increase. The pattern of diastolic owin the descending aorta
was also compared with Qp:Qs and also showed a signicant
relationshipwith antegrade diastolic ow, absent diastolic
ow, and retrograde diastolic ow showing mean Qp:Qs of
1.01:1, 1.3:1, and 1.7:1, respectively. El Hajjar et al
11
per-
formed a similar validation but used superior vena cava
(SVC) ow as a surrogate for Qs to avoid the confounding
shunts. They found that ductal diameter 1.4 mm/kg, LA:Ao
1.4:1, LPA mean velocity 0.42 m/s, or LPA diastolic ve-
locity 0.2 m/s, all predicted an LV output:SVC ratio 4
(approximately, Qp:Qs 2) with more than 90% specicity
and sensitivity.
This still leaves the problem of what is signicant, which
in turn brings us up against the universal paradox of the need
to create arbitrary cutoffs to dichotomize a biological param-
eter, which is naturally a continuum. Nonsignicant and
signicant are probably not good terms to use in the con-
text of a ductal shunt, and it is probably better to categorize
the shunts as closed, small, moderate, and large. From the
above data
10
and using diameter as the primary measure, in a
baby born before 30 weeks with a mainly left-to-right shunt,
ductal diameters 1.5 mm will have shunts of 1.5:1,
which I would call small. Ductal diameters 2 mm will usu-
ally have over twice as much pulmonary owas systemic ow
(Qp:Qs 2:1), which I would call large. Between these 2 is a
group between 1.5 and 2 mm where the shunt will be vari-
able, and I would call it moderate. This classication is a
simplication that has only been validated in the rst post-
natal week. The relationship will weaken as aortopulmonary
pressure differences increase with age. Single ultrasound
measures always have accuracy limitations; so, it is usually
more meaningful to build up the picture not only from the
velocity and direction of ow in the LPA and descending
aorta as described in the preceding text but also by assessing
the impact on the systemic and pulmonary circulations, as
described in the following.
All human injuries are dened by the combination of in-
sult and individual host vulnerability. The categories in the
previous paragraph only allow you to estimate how much
blood is passing through the duct (eg, the insult), it does not
allow you to dene how important that shunt is to that indi-
vidual baby (eg, the vulnerability). Vulnerability is complex
and not easy to dene until after the event of an adverse
outcome. It will vary not only between individuals but also
within the same individual at different ages. However, den-
ing vulnerability starts by describing a hemodynamic milieu
that has a high risk of being pathologic. In broad terms,
possible injury from a left-to-right ductal shunt relates to the
overload of the pulmonary circulation and the drainage of
blood from the systemic circulation.
Overload of the
Pulmonary Circulation
The increase in PBF is essentially a passive process limited
only by ductal size and the pulmonary vascular resistance.
True primary pulmonary hypertension is rare in the preterm
infant and even in the early postnatal hours; the dominant
direction of shunting is left to right. Large PBFs can result
when the ductal constriction fails.
9
Echocardiographic measures of PBF are made complicated
by the intracardiac shunts. The LV output may not represent
PBF because the volume load on the left atrium and resultant
dilatation will drive any shunt through the foramen ovale.
10
Both of these shunts combine to increase PBF, sometimes to
a remarkable degree. Quantitively, or more accurately, semi-
quantitively, the only way to get an estimate of PBF not con-
founded by shunts is to measure the velocities in the root of
the LPA. Normal values for this have been derived in term
babies where mean LPA velocities were usually less then 0.2
m/s.
12
El_Hajjar et al
11
suggested mean LPA velocity above
0.43 m/s suggests a large ductal shunt. This measure may be
confounded by the common physiological narrowing at the
root of the LPA, which causes the blood to accelerate. Expe-
rientially, this narrowing seems uncommon when the duct is
still widely patent, but LPA mean velocities should be inter-
preted with this potential confounder in mind.
Drainage From
the Systemic Circulation
A left-to-right ductal shunt drains more blood from the sys-
temic circulation in systole than it does in diastole; the term
diastolic steal is one of the great misnomers in neonatology.
Although the amount drained is passive, the cardiac compen-
sation for the drainage is not and depends on the ability of the
left ventricle to increase its output to compensate for this
continuous sump of blood out of the systemic circulation.
This is complex, and ultrasound approaches to this depend
on your bias as to whether central or peripheral measures of
blood ow are more important.
In our studies using SVCowas a measure of SBF, preterm
babies were particularly vulnerable to low SBF in the rst 12
hours of life.
9
This low-SBF state is signicantly associated
with a range of adverse clinical outcomes. Although imma-
turity is the dominant risk factor, size of the patent ductus
was independently related to low SBF but only in the very
early scans (at a mean of 5 h). After this time, ductal size was
no longer an independent determinant of SBF. Groves et al
13
found the same relationship, but this was not signicant after
controlling for gestation. Within our study,
9
PDA was treated
on the basis of usual clinical criteria, and we studied SBF at
the time of clinical diagnosis and treatment in 27 babies who
118 N. Evans
were at a mean age of 64 hours. All except 2 babies had both
SVC ow and right ventricular output in the normal range.
These data were derived mainly in the rst 2-3 postnatal
days, and there is less systematic study of total SBF in the
context of later or prolonged ductal shunting. There is more
study of peripheral artery Doppler and ows in the later
period, and the literature is consistent that if you compare
organ blood ows in babies with and without a signicant
PDA, the blood ows will be, on average, lower in the babies
with PDA. This is true of cerebral blood ow measured by
Doppler or near infrared spectroscopy (NIRS), but there is
also evidence that the ductal impact on the SBF may be
greater in the postductal regions (eg, mesenteric or renal)
than in the preductal region (eg, cerebral).
13-15
Again, this is
based largely on summary statistics, and with any of these
systemic or organ blood ow parameters, we do not have
good ways of dening what is pathologic in an individual
infant. For example, with peripheral artery Doppler measure-
ments, the dominant effect of the large PDA shunt is the
reduction and eventually reversal of diastolic velocities. This
is often quantied by the resistance index or pulsatility index.
These measures actually reect ow pattern, and not ow
volume, although some clinicians use them as such. These
measures seem to relate to ductal size, as they are really a
more peripheral marker of the changes in owpattern seen in
the descending aorta. They invariably mark a large ductal
shunt, but whether they measure abnormal organ blood ow
is less certain.
16
Clinical Signs and
Symptoms of a PDA
Much harder in dening vulnerability is predicting or den-
ing the clinical or symptomatic impact in an individual baby.
Despite the limitations to our understanding, ultrasound re-
mains the gold standard in PDA diagnosis, although not all
neonatal intensive care units can access this modality in a
timely manner. Ultrasound machines are expensive; the skills
take time to acquire; and there are often political barriers to
the implementation of neonatologist-performed point-of-
care ultrasound. Many neonatal intensive care units are still
dependent on clinical signs for diagnosis, and we are all still
dependent on interpretation of highly nonspecic symptom-
atology to determine the clinical impact of that PDA. The
well-described physical signs of long systolic murmur, in-
creased precordial impulse, and bounding peripheral pulses
have all been tested against echocardiographic diagnosis.
17,18
Independent blinded daily comparisons in the rst week of
life showed that up to day 4 of life, all these clinical signs have
limitations to their accuracy, with most babies with a large
PDAhaving no clinical signs. Fromday 4 onward, the clinical
signs, particularly the murmur, become much more accurate.
So, most large PDAs will eventually become clinically appar-
ent, but the diagnosis will be made late . . . . Whether that
delay matters to the baby feeds into the current controversy
about PDA treatment.
Symptomatology of a PDA is much harder to dene, as all
the proposed symptoms have a range of different causes, and
often, the only way one can dene whether the PDA is caus-
ing the symptom is to close the duct and see if the symptom
goes away. Dealing with the possible symptoms on each side
of the circulation. It is suggested from animal models that
high PBF results in higher ventilator requirements, but stud-
ies of early treatment with indomethacin have shown the
reverse of this.
19,20
This may be due to negative effects from
indomethacins impact on uid balance. For longer-termpul-
monary effects, PDA is consistently associated with chronic
lung disease, but again, early prophylactic treatment does not
reduce chronic lung disease rates.
21
This could again be the
result of a balance of positive and negative effects of the
treatment, but currently, the trial data do not support a caus-
ative role for the duct in most acute or chronic lung disease.
Despite this, many clinicians (including myself) have a strong
impression of an impact of ductal shunting on respiratory
status in individual babies; indeed, this is often what leads to
treatment decisions, particularly ligation. McNamara et al
22
have proposed a ductal staging scheme that combines echo-
cardiographic and other cardiovascular parameters with re-
spiratory criteria. They use this staging to identify babies
most likely to benet from ductal ligation after failure of
medical treatment.
The acute pulmonary effect where there is more convinc-
ing evidence for a causative role for a ductal shunt is pulmo-
nary hemorrhage (PH) or hemorrhagic edema. We described
a strong association between PH and larger ducts and higher
estimated PBF in 12 preterm babies out of a cohort of 126
who developed PH.
23
The mean age at time of PH was 38
hours with a range from 14 to 55 hours, so consistent with
the fact that early impact of ductal shunting may be much
more important than conventional thinking dictates. In sup-
port of this, PHis one of the short-termoutcomes reduced by
prophylactic indomethacin, particularly when the more mi-
nor (probably traumatic) hemorrhage is removed from the
analysis.
24,25
The fact that it occurs in a minority of babies
highlights the issue of differing individual vulnerability in
that an insult that is tolerated by many babies is not tolerated
by a few. Identifying those few is the challenge in devising
therapeutic strategies for the duct. It is too late once a PH has
happened; we need to be able to predict.
Systemic circulation symptoms are even harder to dene.
PDA is associated with global reduction in blood pressure
(not just diastolic pressure),
26
and there is evidence that
blood pressure improves after treatment.
27
As stated previ-
ously, early PDA shunting is associated with low SBF, but
clinical signs of SBF, including blood pressure, are of limited
accuracy. We found strong associations between early ductal
size and intraventricular haemorrhage (IVH), probably me-
diated through low SBF, but again, by the time the IVH has
happened, it is too late.
9
Biomarkers and the PDA
About 10 years ago, biomarkers were introduced into this
uncertain mix. There are essentially 3 biomarkers that have
Diagnosis of the preterm patent ductus arteriosus 119
been studied in the recent literature; cardiac troponin T
(TnT), atrial natriuretic peptide (ANP), and BNP. TnT is a
marker of myocardial injury and so probably reects patho-
logic consequences of the preterm transitional circulation,
including failure of ductal constriction.
9
ANP is released by
atrial myocytes, whereas BNP is released from the ventricles
of the heart in response to volume and pressure loading. Of
these, BNP looks the most promising for having a clinical
application, rst because of good correlations with echo
markers of ductal shunting, but probably more importantly,
it can be assayed with commercially available bedside testing
kits.
BNP and the Preterm Duct
BNP is produced by the ventricles, in response to stress, in
the formof pro-BNP. This inactive precursor is cleaved into
BNP and the inactive N-terminal pro-BNP (NTpBNP).
Both have a limited half-life: BNP, about 20 minutes, and
NTpBNP, about an hour. BNP reduces intravascular volume
(and so ventricular loads) by causing diuresis and vasodila-
tation.
28
With the introduction of a bedside testing kit, this
measure developed to potential for real clinical utility. The
research that recognized the potential diagnostic role for pre-
term PDA followed:
BNP and Diagnosis of PDA
Several studies have shown good correlation between mark-
ers of PDAshunting and BNP levels, particularly after the rst
48 hours. Puddy et al
29
explored BNP levels on days 3, 5, and
7 in 18 preterm babies with an echo for signicant PDA on
day 7 as the outcome variable. The 6 babies with PDA had
signicantly higher BNP levels on day 3 than the other 12
babies (2012 vs 42 pg/mL, P 0.0001). They also noted that
BNP levels fell after spontaneous or therapeutic closure of the
duct. Choi et al
30
measured BNP levels on day 3 in a cohort of
66 preterm babies that they followed prospectively from this
time with echo; BNP levels in babies who developed a signif-
icant PDA (dened from clinical and echocardiographic cri-
teria) had signicantly higher BNP (2896 pg/mL) levels com-
pared with those with asymptomatic PDA (489 pg/mL) and
those with closed PDA (82 pg/mL). The receiver operator
curve (ROC) for diagnosis of signicant PDA was an impres-
sive 0.997 with the best cutoff at 1110 pg/mL. Flynn et al
31
found positive correlations between BNP levels and echocar-
diographic markers of ductal shunt; the best correlation was
found with measures of ductal diameter. They describe a
postnatal age effect with correlations in paired analyses after
48 hours being much better than those before 48 hours. This
study suggested a lower cutoff of 300 pg/mL but differs from
the study by Choi et al in not including clinical criteria.
Sanjeev et al
32
enrolled babies at clinical suspicion of PDA
(median day 7) and also found high BNP levels associated
with PDA (509 vs 60 pg/mL). Again this study showed that
BNP levels dropped after PDA closure. They, however, pro-
pose another cutoff of 70 pg/mL for the best diagnostic accu-
racy. El-Khuffash et al
33
explored the role of the inactive
by-product NTpBNP by measuring levels at 12 and 48 hours
and comparing with paired echo duct ndings. There were
no differences in NTpBNP at 12 hours between those with
and without an sPDA, but by 48 hours, there were signicant
differences (mean levels 6792 vs 1127 pmol/L). They con-
structed an ROC curve for the 48-hour level of 0.866 with a
cutoff of 5000 pmol/L. Those with sPDA were treated, and
like the other studies, they showed that NTpBNP fell after
treatment (mean 1199 pmol/L). Chen et al
34
also found that
the BNP level at clinical suspicion of PDA had good discrim-
inating power for moderate/large shunts, but when they fol-
lowed individual changes in BNP levels serially, these re-
ected changes in PDA shunt magnitude with less accuracy.
So, overall there are consistent data that babies with larger
PDAs will have signicantly higher BNP levels. There are
limitations to the diagnostic accuracy, but it improves after
day 2. The wide range of different cutoffs is confusing and not
really explained in the literature. This may limit applicability
of this test in the clinical environment.
BNP and Predicting
Need for PDA Treatment
The study of Choi et al
30
, described earlier, explored a com-
bination of diagnosis and prediction of need for treatment. In
a similarly designed study, Czernick et al
35
measured BNP
levels between 24 and 48 hours in 67 preterm babies and
explored the ability to predict need for treatment based on
echo criteria and continued need for ventilation. Babies who
needed treatment had higher BNP levels on day 2 (1069 vs
247 pg/mL). Their ROC curve for BNP was 0.86 with a sug-
gested optimal cutoff of 550 pg/mL. Interestingly, the best
predictive accuracy was found when BNP was combined with
an echo measure of ductal diameter 1.5 mm.
BNP and Response to Medical Treatment
Several studies, including those already discussed, have
noted that BNP levels fall again after successful medical treat-
ment of PDA. This has led to further study to evaluate the
value of BNP level in predicting treatment response. Attridge
et al
36
evaluated the use of BNP to limit dose exposure during
treatment with indomethacin. Sixty babies were randomly
assigned to have BNP measurements before the second and
third dose of indomethacin; if BNP levels were below 100
pg/mL, the dose was withheld. The BNP-guided group re-
ceived less doses of indomethacin (70 vs 88) without differ-
ences in clinical outcomes. Hsu et al
37
provided further sup-
port for this rationale by showing that mean BNP levels were
higher in babies with nonresponsive PDAs than those that
constricted or closed (2234 vs 983 pg/mL). Hammerman et
al
38
looked at NTpBNP levels as a predictor of response and
found there were no differences in baseline levels between
responders and nonresponders. Although there was some
suggestion that levels did not fall (or sometimes increased) in
nonresponders, they concluded that NTpBNP levels were not
sufciently sensitive to use as a clinical tool. Bagnoli et al
39
also found high variability in NTpBNP both at baseline and in
120 N. Evans
response to treatment, but a decrease of more than 80% in
NTpBNP was a reliable index of PDA closure.
BNP Levels and Clinical Outcomes
El-Khuffash and colleagues performed echo and measured
TnT and NTpBNP levels at 12 and 48 hrs. They found babies
who had a PDA at 48 hours and died or developed major IVH
had signicantly higher TnT and NTpBNP levels at 48 hours
than the other babies.
40
They then followed this cohort and
related death or severe/moderate disability at 2 years to
higher PDA score, higher NTpBNP levels (9209 vs 1664
pmol/L) and higher TnT levels (2.3 vs 0.19 g/L), all at 48
hours.
41
ANP, TnT, and the Patent Duct
There has been less work on these biomarkers although ANP
was the rst of the natriuretic peptides to be studied in this
regard. Most recently, Holstrom et al
42
compared both Nt-
ProANP and BNP levels in relation to ductal shunting and
found a strong correlation with the levels of the two peptides.
They also showed similar diagnostic accuracy for echocardio-
graphically signicant PDA. El-Khuffash et al
43
studied TNT
levels in relation to PDA and found signicantly higher levels
at 48 hours in babies with signicant PDA (0.43 vs 0.13
g/L). They speculate that these raised levels may reect
myocardial damage. The study also showed that cTNT levels
fell after successful treatment.
Ultrasound, Biomarkers, or Clinical Signs?
Ultrasound is and remains the gold standard in PDA diagno-
sis. When one has immediate access to ultrasound, it seems
reasonable to ask: why do a blood test when you can look?
However, not everyone has this immediate access, and it is
this situation in which the biomarkers may have a clinical
role. The BNP literature is not easy to condense into a simple
clinical message. BNP measures seem to offer reasonable di-
agnostic accuracy but not early after birth, becoming more
accurate fromday 3. However, the literature proposes a range
of different diagnostic cutoffs, which is difcult for someone
who does not perform research in the eld to understand.
This by itself will limit clinical applicability. The levels seem
to fall with treatment, but the studies vary in the consistency
with which this fall predicts successful treatment.
BNP levels do not seem to achieve their diagnostic accu-
racy until at least day 3, and it should be noted that clinical
signs will lag not far behind this, as they become quite accu-
rate from day 4 onward. So it is really in the early prediction
of ductal closure that echocardiography retains diagnostic
superiority over both biomarkers and clinical signs. Figure 7
shows the diameter of the ductus at an average of 5 hours of
age in a cohort of 126 babies born before 30 weeks.
23
The
range of constriction at all gestations is apparent. In this
study, PDA was treated by usual clinical criteria, for example,
development of physical signs and symptoms, usually respi-
ratory. The lled-in data points in Fig. 7 showthe babies who
were eventually treated for clinically apparent PDA. It can be
seen that almost all those eventually treated were above the
median diameter at 5 hours of age; in other words, they had
below-average postnatal constriction. Linking this with the
concept that the hemodynamic impact of ductal shunting
may be happening much earlier than has been traditionally
thought, it can be seen that the variation shown in Fig. 7 may
offer a method by which we can target early treatment of PDA
at babies who are most likely to benet. A trial to test this
hypothesis is currently under way.
There is some evidence that when BNP levels are com-
bined with echo measures, this may increase the diagnostic
and prognostic utility of both modalities.
40,41
This reects a
universal reality of medical diagnosis, where we often com-
bine different diagnostic approaches to built up a picture and
more diagnostic certainty. So, the question is not really which
of ultrasound, biomarkers, and clinical signs is best, but
rather, how we can use them all to get the best outcomes for
the babies we look after.
References
1. Evans NJ, Kluckow M: Early signicant ductal shunting and intraven-
tricular haemorrhage in ventilated preterm infants. Arch Dis Child
75:F183-F186, 1996
2. Kluckow M, Evans N: Ductal shunting, high pulmonary blood ow,
and pulmonary haemorrhage. J Pediatr 137:68-72, 2000
3. Noori S, McCoy M, Friedlich P, et al: Failure of ductus arteriosus
closure is associated with increased mortality in preterm infants. Pedi-
atrics 123:e138-e144, 2009
4. Benitz WE: Treatment of persistent patent ductus arteriosus in preterm
infants: Time to accept the null hypothesis? J Perinatol 30:241-252,
2010
5. Bose CL, Laughon MM: Patent ductus arteriosus: Lack of evidence for
common treatments. Arch Dis Child Fetal Neonatal Ed 92:F498-F502,
2007
6. Laughon MM, Simmons MA, Bose CL: Patency of the ductus arteriosus
in the premature infant: Is it pathologic? Should it be treated? Curr
Opin Pediatr 16:146-151, 2004
7. de Waal KA, Zonnenberg I: The denition of a hemodynamic signi-
Figure 7 The range of ductal constriction at 5 h of age for each
gestation in a cohort of 126 babies born before 30 weeks. The dotted
line represents the median, and the lled-in triangles represent ba-
bies who later developed a clinically apparent persistent ductus
arteriosus.
Diagnosis of the preterm patent ductus arteriosus 121
cant duct in randomized controlled trials: A systematic literature
review. Acta Paediatr (in press)
8. Evans NJ, Archer LN: Postnatal circulatory adaptation in term and
healthy preterm newborns. Arch Dis Child 65:24-26, 1990
9. Kluckow M, Evans NJ: Low superior vena cava ow and intraventric-
ular haemorrhage in preterm infants. Arch Dis Child 82:F188-F194,
2000
10. Evans N, Iyer P: Assessment of ductus arteriosus shunting in preterm
infants supported by mechanical ventilation: Effect of inter-atrial
shunting. J Pediatr 125:778-785, 1994
11. El Hajjar M, Vaksmann G, Rakza T, et al: Severity of the ductal shunt: A
comparison of different markers. Arch Dis Child Fetal Neonatal Ed
90:F419-F422, 2005
12. Gournay V, Cambonie G, Roz JC: Doppler echocardiographic assess-
ment of pulmonary blood ow in healthy newborns. Acta Paediatr
87:419-423, 1998
13. Groves AM, Kuschel CA, Knight DB, et al: Does retrograde diastolic
ow in the descending aorta signify impaired systemic perfusion in
preterm infants? Pediatr Res 63:89-94, 2008
14. Lemmers PM, Toet MC, van Bel F: Impact of patent ductus arteriosus
and subsequent therapy with indomethacin on cerebral oxygenation in
preterm infants. Pediatrics 121:142-147, 2008
15. El-Khuffash A, Higgins M, Walsh K, et al: Quantitative assessment of
the degree of ductal steal using celiac artery blood ow to left ventric-
ular output ratio in preterm infants. Neonatology 93:206-212, 2008
16. Evans N, KluckowM, Simmons M, et al: Which to measure, systemic or
organ blood ow? Middle cerebral artery and superior vena cava owin
preterminfants. Arch Dis Child Fetal Neonatal Ed 87:F181-F184, 2002
17. Skelton R, Evans N, Smythe J: A blinded comparison of clinical and
echocardiographic evaluation of the preterm infant for patent ductus
arteriosus. J Paediatr Child Health 30:406-411, 1994
18. Davis P, Turner-Gomes S, CunninghamK, et al: Precision and accuracy
of clinical and radiological signs in premature infants at risk of patent
ductus arteriosus. Arch Pediatr Adolesc Med 149:1136-1141, 1995
19. Van Overmeire B, Van de Broek H, Van Laer P, et al: Early versus late
indomethacin treatment for patent ductus arteriosus in premature in-
fants with respiratory distress syndrome. J Pediatr 138:205-211, 2001
20. Schmidt B, Roberts RS, Fanaroff A, et al: Indomethacin prophylaxis,
patent ductus arteriosus and the risk of bronchopulmonary dysplasia:
Further analyses from the Trial of Indomethacin Prophylaxis in Pre-
terms (TIPP). J Pediatr 148:730-734, 2006
21. Fowlie PW, Davis PG, McGuire W: Prophylactic intravenous indo-
methacin for preventing mortality and morbidity in preterm infants.
Cochrane Database Syst Rev 7:CD000174, 2010
22. McNamara PJ, Sehgal A: Towards rational management of the patent
ductus arteriosus: The need for disease staging. Arch Dis Child Fetal
Neonatal Ed 92:F424-F427, 2007
23. Kluckow M, Evans N: Ductal shunting, high pulmonary blood ow,
and pulmonary haemorrhage. J Pediatr 137:68-72, 2000
24. Schmidt B, Davis P, Moddemann D, et al: Trial of Indomethacin Pro-
phylaxis in Preterms Investigators: Long-term effects of indomethacin
prophylaxis in extremely-low-birth-weight infants. New E J Med 344:
1966-1972, 2001
25. Alfaleh K, Smyth JA, Roberts RS, et al: Trial of Indomethacin Prophy-
laxis in Preterms Investigators: Prevention and 18-month outcomes of
serious pulmonary hemorrhage in extremely low birth weight infants:
results from the trial of indomethacin prophylaxis in preterms. Pediat-
rics, 2008 121:e233-e238
26. Evans N, Moorcraft J: Effect of patency of the ductus arteriosus on
blood pressure in very preterm infants. Arch Dis Child 67:1169-1173,
1992
27. Evans N, Iyer P: Change in blood pressure after treatment of patent
ductus arteriosus with indomethacin. Arch Dis Child 68:584-587,
1993
28. El-Khuffash A, Molloy EJ: Are B-type natriuretic peptide (BNP) and
N-terminal-pro-BNP useful in neonates? Arch Dis Child Fetal Neonatal
Ed 92:F320-F324, 2007
29. Puddy VF, Amirmansour C, Williams AF, et al: Plasma brain natriuretic
peptide as a predictor of haemodynamically signicant patent ductus
arteriosus in preterm infants. Clin Sci 103:75-77, 2002
30. Choi BM, Lee KH, Eun BL, et al: Utility of rapid B-type natriuretic
peptide assay for diagnosis of symptomatic patent ductus arteriosus in
preterm infants. Pediatrics 115:e255-e261, 2005
31. Flynn PA, da Graca RL, Auld PA, et al: The use of a bedside assay for
plasma B-type natriuretic peptide as a biomarker in the management of
patent ductus arteriosus in premature neonates. J Pediatr 147:38-42,
2005
32. Sanjeev S, Pettersen M, Lua J, et al: Role of plasma B-type natriuretic
peptide in screening for hemodynamically signicant patent ductus
arteriosus in preterm neonates. J Perinatol 25:709-713, 2005
33. El-Khuffash AF, Amoruso M, Culliton M, et al: N-terminal pro-B-type
natriuretic peptide as a marker of ductal haemodynamic signicance in
preterm infants: A prospective observational study. Arch Dis Child
Fetal Neonatal Ed 92:F421-F422, 2007
34. Cen S, Tacy T, Clyman R: How useful are B-type natriuretic peptide
measurements for monitoring changes in patent ductus arteriosus
shunt magnitude. J Perinatol 30:780-785, 2010
35. Czernik C, Lemmer J, Metze B, et al: B-type natriuretic peptide to
predict ductus intervention in infants 28 weeks. Pediatr Res 64:286-
290, 2008
36. Attridge JT, Kaufman DA, Lim DS: B-type natriuretic peptide concen-
trations to guide treatment of patent ductus arteriosus. Arch Dis Child
Fetal Neonatal Ed 94:F178-F182, 2009
37. Hsu JH, Yang SN, Chen HL, et al: B-type natriuretic peptide predicts
responses to indomethacin in premature neonates with patent ductus
arteriosus. J Pediatr 157:79-84, 2010
38. Hammerman C, Shchors I, Schimmel MS, et al: N-terminal-pro-B-type
natriuretic peptide in premature patent ductus arteriosus: A physiolog-
ical biomarker but is it a clinical tool? Pediatr Cardiol 31:62-65, 2010
39. Bagnoli F, Rossetti A, Casucci M, et al: Amino terminal B-type natri-
uretic peptide in the therapy of patent ductus arteriosus. Minerva Pe-
diatr 62:67-70, 2010
40. El-Khuffash A, Barry D, Walsh K, et al: Biochemical markers may iden-
tify preterminfants with a patent ductus arteriosus at high risk of death
or severe intraventricular haemorrhage. Arch Dis Child Fetal Neonatal
Ed 93:F407-F412, 2008
41. El-Khuffash AF, Slevin M, McNamara PJ, et al: Troponin T, N-terminal
pro natriuretic peptide and a patent ductus arteriosus scoring system
predict death before discharge or neurodevelopmental outcome at 2
years in preterm infants. Arch Dis Child Fetal Neonatal Ed 96:F133-
F137, 2011
42. Holmstrm H, Hall C, Thaulow E: Plasma levels of natriuretic peptides
and hemodynamic assessment of patent ductus arteriosus on preterm
infants. Acta Paediatr 90:184-191, 2001
43. El-Khuffash AF, Molloy EJ: Inuence of a patent ductus arteriosus on
cardiac troponin T levels in preterm infants. J Pediatr 153:350-353,
2008
122 N. Evans