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Original article

Peak systolic to end diastolic flow velocity ratio


is associated with ductal patency in infants below
32 weeks of gestation
A Smith,1 M Maguire,2 V Livingstone,1,3 E M Dempsey1,3

▸ Additional material is ABSTRACT


published online only. To view Background Early diagnosis and effective treatment of What is already known on this topic
please visit the journal online
(http://dx.doi.org/10.1136/
the patent ductus arteriosus (PDA) in infants less than
archdischild-2014-306439). 32 weeks gestation remains contentious.
▸ Controversy surrounds the diagnosis and
1 Objective To determine which clinical and
Department of Paediatrics and treatment of a patent ductus arteriosus.
echocardiographic parameters are associated with PDA
Child Health, Neonatal ▸ Gestational age predicts closure.
Intensive Care Unit, University patency in preterm infants less than 32 weeks gestation.
College Cork, Cork, Ireland
2
Design/Methods This was a prospective cohort study.
Department of Cardiology, An echocardiography (echo) was performed within
Cork University Hospital, Cork,
12–48 h of birth and a follow-up echo at 1 month
Ireland What this study adds
3
Infant Centre, University of life. Parental consent was obtained.
College Cork, Cork, Ireland Results 55 babies were enrolled. Median (range)
gestation was 28 (24–31) weeks and birth weight ▸ Interrogation of ductus should include
Correspondence to quantification of the systolic and diastolic flow
1090 g (470–1800 g). ECHO 1 demonstrated that 50
Dr Eugene M Dempsey,
Department of Paediatrics and babies had a PDA present within 48 h of birth, of which velocities.
Child Health, Neonatal 19 were large (≥2 mm) (36%) and 31 were small (59%) ▸ The peak systolic to end diastolic flow velocity
Intensive Care Unit, University on colour Doppler assessment of duct diameter. Three ratio was the best echo parameter to predict
College Cork, Cork, Ireland; babies died before 1 month. At 1 month 30 babies still ductal patency in the preterm infant.
gene.dempsey@hse.ie
had a PDA (58%), 10 of which were large (19%) and
Received 20 March 2014 19 were small (36%). Parameters significantly associated (IVH) and pulmonary haemorrhage but no dffer-
Revised 10 October 2014 with large PDAs versus no PDA at 1 month were ence in long-term outcome. There have been two
Accepted 19 October 2014 gestational age (26 weeks vs 30 weeks, p=0.002), birth
Published Online First large ibuprofen prophylactic trials.11 12 While there
18 November 2014
weight (860 g vs 1290 g, p=0.007) and ventilator was a reduction in the need for surgical ligation in
support at 48 h (80% vs 17%, p=0.001). Echo the Gournay trial, there was no difference in mor-
parameters revealed that ductal size on colour Doppler tality and the trial was stopped early because of
(2.5 mm vs 1.5 mm, p=0.003), end diastolic flow velocity safety concerns in the treatment arm.11 Van
(57 m/s vs 147 m/s, p<0.001) and peak systolic to end Overmeire et al12 found no difference in the
diastolic flow velocity ratio (2.29 vs 1.23, p=0.001) at primary outcome of IVH but did identify a statistic-
48 h were associated with large PDAs at 1 month. ally significant reduction in the incidence of PDA
Conclusions For infants less than 32 weeks gestation a and a non-significant reduction in the need for sur-
peak systolic to end diastolic flow velocity ratio>2 within gical ligation. Each of these prophylactic studies
48 h of birth is associated with a persistent large PDA at had placebo arms: incidence of spontaneous PDA
1 month of age. closure in TIPP was 50%, in the Gournay study
45% and in the Van Overmeire study 60%. Much
of the variation relates to the gestational age, Koch
having noted a spontaneous closure rate of
INTRODUCTION approximately 34% in extremely low gestational
The diagnosis and subsequent management of a age newborns in the 1st week of life.16
patent ductus arteriosus (PDA) in the very preterm The management of the ductus remains unre-
infant remains contentious.1 Many different diag- solved.17 Various algorithms have been developed in
nosic criteria have been proposed including various an attempt to identify newborns with spontaneous
echocardiographic,2–5 biochemical6–8 and clinical closure and thereby avoid unnecessary medical inter-
parameters9 or combinations of these. Various vention. These often incorporate clinical, biochem-
interventions have been advocated including ical and echocardigraphic parameters.3 7 18–20 Early
prophylactic medical treatment with indometh- treatment is more likely to result in a higher closure
acin10 or ibuprofen,11 12 early surgical closure,13 an rate and hence the need to identify patients early if
early targeted echocardiography (echo) approach,14 one is to adopt a targeted approach. Therefore the
a symptomatic approach and finally a more conser- aim of this study was to identify clincial and ductal
vative approach incorporating respiratory support, paramters within the first 48 h associated with subse-
To cite: Smith A,
fluid restriction and diuretic therapy.15 quent ductal patency at 1 month of age.
Maguire M, Livingstone V, The Trial of Indomethacin Prophylaxis in
et al. Arch Dis Child Fetal Preterms (TIPP) trial10 has shown a reduction in METHODS
Neonatal Ed 2015;100: the number of infants who required PDA ligation, a A prospective, observational study was conducted
F132–F136. reduction in severe intraventricular haemorrhage at the Neonatology Department of Cork University
F132 Smith A, et al. Arch Dis Child Fetal Neonatal Ed 2015;100:F132–F136. doi:10.1136/archdischild-2014-306439
Original article

Maternity Hospital, Cork, Ireland over a 12 month period from echo 1 demonstrated that 50 babies have a PDA (96%), of which
December 2011 to November 2012. All newborns less than 19 were ≥2 mm on colour Doppler (36%) and 31 were less than
32 weeks old were eligible for inclusion in this study. Patients 2 mm (60%). At 1 month 30 babies still had a PDA (58%), 10 of
with complex cardiac malformations and/or gross congenital which were large (19%) and 19 were small (36%). The PDA was
abnormalities were excluded. Parental consent was obtained. not present in 23 (44%) babies. The results are presented accord-
The Cork Research and Ethics Committee of the Cork Teaching ing to this allocation in tables 1 and 2. Only one baby received
Hospitals approved this study. ibuprofen at 5 days of age and ultimately had a PDA ligation per-
All eligible infants underwent echo by a consultant neonatolo- formed at 1 month of age. There were 26 infants with a gesta-
gist within the first 48 h of life (ECHO 1). At 1 month of life all tional age up to 28+6 weeks.
babies had a second echo (ECHO 2) performed by an echo Tables 1 and 2 display the clinical and echo data at the time
technician who was unaware of the original study findings. of the original echo performed within first 48 h of life. Clinical
Babies may have had additional echos in the interim period as characteristics that were associated with PDA group were gesta-
clinically indicated by the attending clinician who was unaware tional age, birth weight, mean airway pressure (MAP), lactate at
of the original echocardiographic findings. The Philips HE11XE 12 h, 1 min Apgar value and ventilation status. No patient had a
ultrasound scanner with curved array transducer (5–8 MHz) or pulmonary haemorrhage. Pairwise comparisons revealed that
sector array transducer (4–12 MHz) incorporating colour flow the differences were only between the no PDA group and the
and pulsed wave Doppler with adaptive Doppler technology large PDA group for birth weight and lactate at 12 h, between
was used. The scan was recorded on the hard disk of the ultra- the small and no PDA group for MAP, while the differences
sound machine and these were subsequently electronically were between the no PDA group and the large PDA group and
exported for later measurements. Structural normality of the the no PDA group and the small PDA group for gestational age
heart was confirmed and the following standard echo para- and ventilation status.
meters were recorded: Echo characteristics that were associated with the PDA group
▸ PDA diameter on colour Doppler; were duct size on colour assessment, systolic and diastolic flow vel-
▸ PDA diameter on non-colour echo; ocity and their ratio. In the pairwise comparisons, differences were
▸ Left atrium to aortic ratio; found between the large PDA group and the no PDA group and the
▸ Peak systolic flow velocity across ductus; small PDA group for duct size and ratio while for systolic flow vel-
▸ End diastolic flow velocity across ductus; ocity, the differences were between the no PDA group and the large
▸ Peak systolic to end diastolic flow ratio (ductal pattern); PDA and small PDA groups. Diastolic flow velocity was significantly
▸ Diastolic flow velocity pattern in pulmonary artery. different between the large PDA group and the small PDA group.
The following clinical and physiological data were recorded: Ratio was the best performing ECHO parameter in discriminating
Gestation, birth weight, respiratory support, and vital signs between those with a large PDA and those with a small or no PDA
including heart rate and blood pressure and biochemical para- with an area under the ROC curve of 0.89 and positive predictive
meters (lactate and base excess) were recorded within the first value of 72.7% (table 3). Figure 1 displays the ROC for ratio.
48 h of life. At 1 month babies were categorised into three When we analysed babies less than 29 weeks the area under the
groups based on ductal presence and size21: large PDA curve (AUC) for ratio was similar (0.87), the specificity increased to
(≥2 mm), small PDA (<2 mm) and those with no PDA. We 93.3% and the positive predictive value (PPV) increased to 85.7%
chose 2 mm as a cut-off to determine a large PDA as this value (see online supplementary table S4), a reflection of the increased
has been considered as representative of a haemodynamically prevalence of PDA in the more immature babies.
significant ductus.21 22
Categorical data was described using frequency ( percentage) DISCUSSION
and continuous data using median (IQR). Differences between We have identified a number of clincial and echocardiographic
the three PDA groups were investigated using the Kruskal-Wallis findings within the first 48 h of life that are associated with the
test and the χ2 test. ECHO parameters were compared between presence of a large PDA at approximately 1 month of age. We
babies with large PDAs and babies with no PDA or a small PDA determined, a priori, a ductal diameter of 2 mm or more would
using receiver operator curve (ROC) curves, and the optimal represent a large patent duct at 1 month of age. The clinical
cut-off value for each parameter was determined using the parameters identifed in the first 48 h were gestational age, birth
Youden index. The diagnostic accuracy of each ECHO parameter weight and need for respiratory support. Gestational age and
using the optimal cut-off was described using sensitivity, specifi- birth weight parameters are consistent with the natural history
city, positive predictive value and negative predictive value. All of the patent ductus, namely an increasing incidence of PDA
statistical analysis was performed using Stata V.13.0 (StataCorp with decreasing gestational age and birth weight. The need for
LP, College Station, Texas, USA). All tests were two-sided and a p ventilator support would be consistent with the concept of a
value <0.05 was considered to be statistically significant. potentially haemodynamically significant duct, although some
babies less than 28 weeks may be ventilated within the first 48 h
RESULTS of life. In a recent survey of practice in French neonatal inten-
Fifty-five babies were enrolled in this study. Three babies were sive care units the need for respiratory support was considered a
excluded from the analysis, one baby died from transfusion criteria consistent with a hamodynamically significant dutcus,23
related acute gut injury on day 10 of life, a second from respira- however the exact timing of this support was not clear. The
tory failure within 12 h secondary to pulmonary hypoplasia and number of infants in our cohort is too small to allow one to
a third infant diagnosed with trisomy 21 was excluded. make any firm conclusions in relation to ventilator support at
Therefore analysis was carried out on 52 babies. The initial echo this time. We did not include clinical signs of a ductus within
performed on the patient with pulmonary hypoplasia revealed this time period, due to their poor correlation with echo para-
severe pulmonary hypertension with pure right to left ductal meters2 and the subjective nature of many of these findings,
shunting. The patient who developed transfusion related acute such as bounding pulses or a murmur. There was no difference
gut had a small PDA on initial echo. Within the first 48 h of birth in any blood pressure parameter recorded.
Smith A, et al. Arch Dis Child Fetal Neonatal Ed 2015;100:F132–F136. doi:10.1136/archdischild-2014-306439 F133
F134

Original article
Table 1 Comparison of clinical characteristics by PDA group
PDA group Pairwise comparisons

adjusted p value
Large PDA (≥2 mm) (a) (n=10) Small PDA (<2 mm) (b) (n=19) No PDA (c) (n=23)
Median (IQR) p Value* a vs b a vs c b vs c

Gestational age (weeks) 26.35 (24.80 to 28.85) 28.28 (26.50 to 30.00) 30.42 (30.07 to 31.07) 0.001 0.740 0.002 0.016
Smith A, et al. Arch Dis Child Fetal Neonatal Ed 2015;100:F132–F136. doi:10.1136/archdischild-2014-306439

Birth weight (g) 860 (680 to 1040) 1050 (870 to 1325) 1290 (1010 to 1525) 0.006 0.490 0.007 0.148
MAP 6.5 (5.0 to 7.0) 7.0 (5.0 to 7.1) 5.0 (4.3 to 5.3) 0.003 1 0.09 0.003
T (°C) on admission 36.75 (36.40 to 36.90) 36.80 (36.40 to 37.05) 36.60 (36.40 to 36.85) 0.733
Lactate at 12 h 4.6 (3.2 to 4.7) 3.2 (2.4 to 4.0) 2.8 (1.9 to 3.5) 0.028 0.270 0.022 0.774
Lactate at 36 h 3.1 (2.1 to 5.7) 2.3 (1.4 to 3.0) 2.0 (1.7 to 2.6) 0.061
Bd in first 12 h 7.95 (6.70 to 10.80) 6.70 (4.80 to 8.50) 5.90 (4.65 to 7.15) 0.059
BP mean (mm Hg) 29.5 (27.0 to 42.0) 30.0 (25.5 to 31.5) 35.0 (29.5 to 41.0)† 0.151
Systolic BP (mm Hg)† 45.5 (37.0 to 47.0) 40.0 (35.0 to 48.0) 49.0 (41.0 to 53.5)† 0.106
1 min Apgar score 4.0 (3.0 to 8.0)‡ 6.0 (4.5 to 8.0) 8.0 (7.5 to 9.0) 0.019 1 0.072 0.054
5 min Apgar score 6.0 (5.0 to 9.0)‡ 9.0 (7.0 to 9.0) 9.0 (9.0 to 9.0) 0.141
n (%) p Value§
Ventilated 8 (80.0) 13 (68.4) 4 (17.4) <0.001 0.675 0.001 0.001
CPAP 9 (90.0) 18 (94.7) 18 (78.3) 0.329
*From Kruskal-Wallis test.
†n=20 in no PDA group.
‡n=9 in large PDA group.
§From Fisher’s exact test.
Bd, base deficit; BP, blood pressure; CPAP continuous positive airway pressure; PDA, patent ductus arteriosus.
Original article

Table 2 Comparison of echocardiography characteristics by PDA group


Pairwise comparisons
PDA group p value

adjusted p value
Large PDA (≥2 mm) Small PDA (<2 mm)
(a) (n=9†) (b) (n=18†) No PDA (c) (n=21†) Overall
Median IQR p value* a vs b a vs c b vs c

LA : Ao 1.07 (1.00 to 1.25) 1.10 (1.00 to 1.20) 1.10 (0.90 to 1.20) 0.839
Duct size—colour (mm) 2.50 (2.20 to 2.90) 1.60 (1.30 to 2.00) 1.50 (1.00 to 1.70) 0.005 0.031 0.003 1
Duct size—non-colour (mm) 2.75 (2.50 to 3.10) 2.20 (1.50 to 2.70) 1.55 (1.10 to 2.20) 0.059
Systolic flow velocity (m/s) 117.50 (88.00 to 131.20) 136.00 (113.40 to 150.00) 170.30 (162.00 to 206.65) 0.005 1 0.008 0.040
Diastolic flow velocity (m/s) 57.20 (37.70 to 60.00) 100.50 (71.30 to 128.70) 147.20 (111.95 to 172.65) 0.001 0.115 <0.001 0.110
Ratio 2.29 (1.98 to 3.01) 1.39 (1.17 to 1.58) 1.23 (1.12 to 1.40) 0.001 0.011 0.001 1
*From Kruskal-Wallis test.
†n=8/18/20 for LA : Ao; n=9/18/21 for duct size colour; n=6/12/18 for duct size non-colour; n=9/17/15 for systolic and diastolic flow; n=9/17/16 for ratio.
PDA, patent ductus arteriosus.

The echo findings consisted of the size of duct identified on restrictive and pulsative flows in the PDA with predictive value of
colour flow doppler and the ratio of the peak systolic to end dia- these observations.
stolic flow velocity ratio (PSEDR). The non-colour assessment of However a notable finding was the systolic to diastolic flow
the ductus was not significant and consistently overestimated the velocity ratio within the ductus was different across the three
actual size of the ductus. We believe this finding reaffirms the groups. This finding is consistent with patterns of ductal flow
importance of appropriate colour flow interrogation of the duct, first described by Su et al4 5 and used susequently in a number
and although colour interrogation is not without its potential of randomised trials.24 25 They described a number of patterns
errors, we believe it allows one to adequately assess the func- including a pulmonary hypertension type pattern, a growing
tional diameter of the ductus. Colour assessment of the ductus pattern, a pulsatile pattern and a restrictive pattern. We believe
should be incorporated and, as can be seen from our findings, that our findings are representative of a pulsatile pattern and
large ducts identified on colour doppler within the first 48 h provide objective measurement of this, rather than a subjective
were associated with patency. Kwinta et al3 evaluated a group of visual assessment. We propose defining a pulsatile pattern as a
60 babies, 16 of whom went on to have PDA ligation and found ratio of systolic to diastolic flow velocity of greater than
that the ductal diameter was 2.6 mm compared with 0.9 mm for 2. We believe that this is a relatively easy assessment to perform
the group that did not require surgery. In our cohort the left at the bedside and is also readily calculable. The finding of a
atrium to aorta (LA : Ao) ratio was not larger in the group that large ductus with a pulsatile flow pattern is consistent with a
maintained patency, this finding was not statistically significant retrospective review perfomed by Condo et al.18 We did not
and the median ratio was lower than that described previously in include babies with evidence of elevated pulmonary pressures as
a number of studies.7 19 This is not surprising considering that all the bidirectional blood flow precluded us from calculating a
our echocardiograms were performed within the first 48 h, a ratio, and generally we would not advocate treatment of a bidir-
time frame in which it was unlikely that the left atrium would ectional flow pattern initially but rather recommend a repeat
become overdistended resulting in a larger diameter detected on echo in the next 24 h prior to considering treatment.
M-mode assessment. Diastolic disturbance in the pulmonary We did not routinely evaluate other echo parameters such as
artery was not associated with patency, and again this may reflect the peak flow velocity in the left pulmonary artery (LPA), LPA :
the time period in which the echocardiograms were perfomed. PDA ratio, left ventricular output (LVO) or LVO : superior vena
The peak systolic velocity of the ductus may also be an inde- cava (SVC) ratio. These measurements have been used previ-
pendent indicator of closure. The narrower the ductus the greater ously as markers of a ‘haemodynamically significant’ PDA and
the systolic velocity across the ductus. Our study identified that a as predictors of ‘symptomatic’ PDA, spontaneous closure or the
lower peak systolic velocity was associated with patency, however necessity for medical intervention. For example, Thankavel
this finding was not statistically significant between the large and reported that ductal diameter, LA : Ao ratio and LPA diastolic
small PDA groups. A low end diastolic flow velocity within the flow velocity were independent predictors of spontaneous
ductus was significantly associated with a large patent ductus at closure, but that the ratio of the PDA : LPA diameters was the
1 month of age. We believe this is the first study to quantify only significant predictor of spontaneous closure.26 In a

Table 3 Diagnostic accuracy of echocardiography characteristics, n=41*


Area under the ROC Sensitivity Specificity Positive predictive Negative predictive
curve (95% CI) Cut-off (95% CI) (95% CI) value (95% CI) value (95% CI)

Large PDA vs small/no PDA


Duct size—colour (mm) 0.82 (0.67 to 0.92) >2.1 77.8 (40.0 to 97.2) 87.5 (71.0 to 96.5) 63.6 (30.8 to 89.1) 93.3 (77.9 to 99.2)
Systolic flow velocity (m/s) 0.73 (0.57 to 0.86) ≤131.2 77.8 (40.0 to 97.2) 75.0 (56.6 to 88.5) 46.7 (21.3 to 73.4) 92.3 (74.9 to 99.1)
Diastolic flow velocity (m/s) 0.85 (0.71 to 0.94) ≤74.7 88.9 (51.8 to 99.7) 81.3 (63.6 to 92.8) 57.1 (28.9 to 82.3) 96.3 (81.0 to 99.9)
Ratio 0.89 (0.76 to 0.97) >1.92 88.9 (51.8 to 99.7) 90.6 (75.0 to 98.0) 72.7 (39.0 to 94.0) 96.7 (82.8 to 99.9)
*n=9 in large PDA group and n=32 in small/no PDA group.
PDA, patent ductus arteriosus.

Smith A, et al. Arch Dis Child Fetal Neonatal Ed 2015;100:F132–F136. doi:10.1136/archdischild-2014-306439 F135
Original article
Competing interests None.
Patient consent Parental consent obtained.
Ethics approval Cork Research and Ethics Committee, Cork, Ireland.
Provenance and peer review Not commissioned; externally peer reviewed.

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Contributors AS had primary responsibility for overall content and manuscript 2014;99:F99–F104.
preparation. She was involved with study design, research collection and research
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study design. VL was involved with the statistical analysis and manuscript 27 Sehgal A, Menahem S. Interparametric correlation between echocardiographic markers
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content, study design, manuscript preparation, research collection and research
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Funding This study was supported by the European Commission within the 7th arteriosus. Acta Paediatr 2011;100:59–66.
Framework Programme (EU FP7/2007-2013) under grant agreement no. 260777 29 Broadhouse KM, Price AN, Durighel G, et al. Assessment of PDA shunt and systemic
(The HIP Trial). blood flow in newborns using cardiac MRI. NMR Biomed 2013;26:1135–41.

F136 Smith A, et al. Arch Dis Child Fetal Neonatal Ed 2015;100:F132–F136. doi:10.1136/archdischild-2014-306439

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