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ADC-FNN Online First, published on February 4, 2015 as 10.1136/archdischild-2014-307930
1
Department of Neonatology,
The Rotunda Hospital, Dublin,
Ireland
2
School of Medicine, Royal
College of Surgeons in Ireland,
Dublin, Ireland
3
Coombe Women and Infants
University Hospital, Dublin,
Ireland
4
Institute for the Care of
Mother and Child, Prague,
Czech Republic
5
The Department of Paediatric
Cardiology, Our Lady’s
Children’s Hospital Crumlin,
Dublin, Ireland
6 What this study adds
UCD School of Medicine and
Medical Sciences, Dublin,
Ireland
Correspondence to
Dr Afif EL-Khuffash,
Department of Neonatology,
The Rotunda Hospital, Parnell
Street, Dublin 1, Ireland;
afif_faisal@hotmail.com
Received 20 November 2014
Revised 6 January 2015
Accepted 14 January 2015
To cite: EL-Khuffash A,
James AT, Cleary A, et al.
Arch Dis Child Fetal
Neonatal Ed Published
Online First: [ please include
Day Month Year]
doi:10.1136/archdischild-
2014-307930
EL-Khuffash A, et al. Arch Dis Child Fetal Neonatal Ed 2015;0:F1–F4. doi:10.1136/archdischild-2014-307930
Copyright Article author (or their employer) 2015. Produced by BMJ Publishing Group Ltd (& RCPCH) under licence.
Short research report
Late medical therapy of patent ductus arteriosus
using intravenous paracetamol
Afif EL-Khuffash,1,2 Adam T James,1 Aoife Cleary,1 Jana Semberova,3,4 Orla Franklin,5
Jan Miletin3,4,6
ABSTRACT
Objective To investigate the effect of late treatment
with intravenous paracetamol on patent ductus arteriosus
(PDA) closure prior to possible PDA ligation.
Methods A retrospective review of infants with a
haemodynamically significant PDA, considered for PDA
ligation and treated with intravenous paracetamol prior to
possible ligation.
Results Thirty six infants with a median gestation of
26.1 weeks received paracetamol at a median age of
27 days. Paracetamol was associated with immediate
closure in nine (25%) infants. There was no response to
paracetamol treatment in four (11%) infants who
subsequently underwent a PDA ligation. In 23 (64%)
infants, the PDA constricted and all but one of this group
demonstrated complete PDA closure prior to discharge.
Conclusions There may be a role for intravenous
paracetamol in late closure of infants with a significant
PDA to avoid ligation. The use of paracetamol for late
treatment of PDA should be systematically evaluated.
INTRODUCTION
Early treatment of patent ductus arteriosus (PDA) in
preterm infants has fallen out of favour in recent
years due to lack of evidence for short-term and long-
term benefits. Although several authors report no
increase in PDA-associated complications using this
approach,1 a persistent ductus arteriosus beyond the
3rd week of life is associated with increased mortality.
Conventional medical therapy using non-steroidal
anti-inflammatory drugs (NSAIDs) does not result in
PDA closure beyond the first few days of life. As a
result, surgical ligation of a persistent, large, haemo-
dynamically significant PDA is still carried out. PDA
ligation results in a reduction in mortality; however,
it is also associated with increased morbidity (chronic
lung disease (CLD), retinopathy of prematurity
(ROP) and neurodevelopmental impairment).2 In
addition, PDA ligation may lead to haemodynamic
instability accompanied by a low cardiac output state
and impaired myocardial performance in the imme-
diate postoperative period.3
Paracetamol may be effective in achieving PDA
closure when used following failure of NSAID
treatment and/or when contraindication to NSAID
treatment occurs. In addition, paracetamol may
possess PDA constricting properties when adminis-
tered beyond the first 2 weeks of life and may be
an alternative option to ligation for closing persist-
ing PDAs.4 At two tertiary neonatal intensive care
units in Dublin, Ireland, we adopt a conservative
approach to PDA treatment. Infants with persistent
ducts beyond the 2nd to 3rd week of life associated
What is already known on this topic
▸ Paracetamol may be effective in achieving
patent ductus arteriosus (PDA) closure in
preterm infants.
▸ Paracetamol is as effective as non-steroidal
anti-inflammatory drugs in early closure of
PDA.
▸ Late treatment with intravenous paracetamol
beyond the 2nd week of life may be effective in
PDA closure.
▸ Late treatment with paracetamol may avoid
PDA ligation.
with clinical and echocardiography features of pul-
monary overcirculation and/or systemic hypoperfu-
sion are referred for PDA ligation. Since October
2012, a trial of intravenous paracetamol is adminis-
tered to those infants prior to the surgical proced-
ure in an attempt to close the PDA. We report the
results of the use of intravenous paracetamol in this
population over a 2-year period.
METHODS
This is a retrospective review of all preterm infants
who were candidates for PDA ligation and received
(intravenous) paracetamol in an attempt to close the
PDA prior to the surgical procedure from the
Rotunda Hospital, and Coombe Women and Infant
University Hospital, Dublin, Ireland. The two units
cater for a combined 20 000 deliveries and approxi-
mately 300 infants less than 1500 g per annum.
Both units currently adopt a conservative, non-
pharmacological approach to PDA management.
NSAIDs are not administered in the first 7 days of
life due to the equivocal nature of the evidence
regarding early PDA treatment. Infants are consid-
ered for PDA ligation if the duct persists beyond the
2nd week of life and is haemodynamically signifi-
cant. This must be accompanied by echocardio-
graphic evidence of pulmonary overcirculation and
systemic hypoperfusion along with clinical features
attributable to the PDA based on a triaging system
published by our group.3 All infants in this review
were candidates for PDA ligation as they fulfilled
both the echocardiography and/or the clinical
F1
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Short research report

criteria of the triaging system.3 They failed a trial of ibuprofen, PDA treatment with paracetamol was also associated with a
had a contraindication to its use, or were beyond 3 weeks of age significant increase in diastolic blood pressure and aortic and
where ibuprofen is not known to be effective. Since October MCA end diastolic flow. There was no change in any of the
2012, candidates for PDA ligation undergo a trial of intravenous function parameters following treatment (table 2). There was a
paracetamol at a dose of 60 mg/kg/day in four divided doses high incidence of NEC (31%) and CLD in survivors (81%). In
(Paracetamol Actavis IV, 10 mg/mL. Actavis, Little Island, Co, all but one case of NEC, the condition developed prior to the
Cork, Ireland). Echocardiography is carried out following 3 days commencement of paracetamol (see below).
of treatment and the course is continued for a further 3 days if Four infants died before discharge at an age ranging between
the PDA remains open. Paracetamol was given for a maximum of 32 and 50 days post-delivery. The median time between the
6 days regardless of PDA status. Only one course of paracetamol receipt of paracetamol and death was 23 days. In three infants,
was given ranging from 3 to 6 days. All infants undergo an echo- withdrawal of life-sustaining treatment was carried out due to a
cardiography assessment after completion of the treatment poor neurodevelopmental outcome (two due to severe grade 4
course and before hospital discharge. intraventricular haemorrhage and severe cystic periventricular
The following clinical information was collected for every leukomalacia (PVL), and one due to severe cerebral develop-
infant: gestation and birth weight; previous use of NSAIDs; con- mental abnormalities, including lissencephaly and bilateral
traindications to NSAIDs use; age and weight at paracetamol hydrocephalus). One infant died from fulminant NEC occurring
treatment; duration of paracetamol treatment and reason for 2 weeks after the completion of the paracetamol course. All the
PDA treatment. Clinical outcomes prior to discharge were also ligated infants survived to discharge.
collected and included PDA ligation, CLD (defined as the need
for oxygen at 36 weeks corrected gestational age), radiologically
confirmed necrotising enterocolitis (NEC), ROP requiring treat- Table 1 Clinical characteristics and outcome data for the cohort
ment, duration of ventilation, duration of hospital stay and
Median [IQR] or
death.
count (%)
In both centres, echocardiography assessment of PDA signifi-
cance was performed before and after paracetamol treatment Gestation at birth (weeks) 26.1 [24.6–27.9]
using GE Vivid I (GE Medical, Milwaukee, Wisconsin, USA), or Birth weight (g) 773 [645–954]
Phillips HD11 Ultrasound System (Andover, Massachusetts, Male 21 (58)
USA). The following echocardiography parameters were col- Small for gestation (<10th centile) 10 (28)
lected before and after treatment: PDA diameter (measured in Caesarean section 27 (75)
2D at the pulmonary end); peak pressure gradient across the Five minute Apgar score 8 [7–9]
PDA; markers of pulmonary overcirculation (left atrium: aortic Chorioamnionitis 5 (14)
(LA:Ao) ratio, left ventricular output); markers of systemic Pre-eclampsia 3 (8)
hypoperfusion (abdominal aortic and middle cerebral artery Magnesium sulfate 30 (83)
(MCA) end diastolic velocity) and shortening fraction (SF). In Antenatal steroids (full course) 30 (83)
addition, tissue Doppler velocities of the left and right ventricles Intraventricular haemorrhage (IVH) (grades 3 and 4) 3 (8)
were collected on 21 infants. The techniques used for obtaining Culture positive sepsis 14 (39)
all those measurements are described elsewhere.5 Treatment parameters
Continuous data were presented as medians and IQRs, and Age at treatment (days) 27 [16–39]
categorical data as absolute values and percentages. Paired data Corrected gestation (weeks) 29.3 [28.1–32.9]
were compared using Wilcoxon signed-rank test. Categorical Duration of treatment (days) 5 [3–6]
data were compared using the χ2 test or Fischer’s exact test as Weight at treatment (g) 1032 [878–1492]
appropriate. Previous use of ibuprofen 10 (28)
Primary reason for using paracetamol
Beyond 3 weeks of age* 13 (36)
RESULTS Necrotising enterocolitis 11 (31)
Thirty-six infants (15 from the Coombe and 21 from the Failure of ibuprofen* 8 (22)
Rotunda) with a median [IQR] gestation and birth weight of IVH 3 (8)
26.1 [24.6–27.9] weeks and 773 [645–954] g received paraceta- Thrombocytopenia 1 (3)
mol at a median age of 27 [16–39] days for PDA closure during Outcome data
the study period. Their clinical characteristics and outcomes are Reintubation rate 2 [1–4]
presented in table 1. IPPV days 27 [9–37]
The administration of paracetamol was associated with imme- CPAP days 35 [26–46]
diate closure in nine infants (25%), none of which reopened Oxygen days 29 [17–72]
prior to discharge. There was no response to paracetamol treat- Time to full feeds (days) 14 [10–31]
ment in four infants (11%), all of whom subsequently under- Retinopathy of prematurity 12 (33)
went a PDA ligation. In the remaining 23 infants (64%), the Periventricular leukomalacia 5 (14)
PDA constricted by a median of 0.9 [0.5–1.9] mm immediately Chronic lung disease (in survivors) 26 (81)
post-treatment and all but one infant demonstrated complete PDA ligation 4 (11)
PDA closure prior to discharge. A total of 10 infants received Hospital stay (days) 92 [80–110]
ibuprofen prior to paracetamol treatment. In this cohort, ibu- Death before discharge 4 (11)
profen did not result in PDA closure in any of the infants. Four *Two infants who were beyond 3 weeks of age also received ibuprofen making the
of the nine infants exhibiting complete PDA closure (44%) were total of infants receiving (and failing) ibuprofen 10.
pretreated with ibuprofen. In the remaining 27 infants, six CPAP, continuous positive pressure ventilation; IPPV, invasive positive pressure
ventilation; PDA, patent ductus arteriosus.
(22%) were pretreated with ibuprofen.
F2 EL-Khuffash A, et al. Arch Dis Child Fetal Neonatal Ed 2015;0:F1–F4. doi:10.1136/archdischild-2014-307930
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Short research report

Table 2 Clinical cardiorespiratory and echocardiography parameters before and after paracetamol treatment
Pretreatment Post-treatment p Value

Heart rate 160 [157–174] 160 [148–170] 0.9

Blood pressure (mm Hg)
Systolic 63 [57–70] 61 [55–78] 0.9
Diastolic 31 [29–38] 37 [29–47] 0.009
Use of inotropes 1 (3) 0 (0) NA
Ventilation
None 2 (6) 3 (8) 0.6
CPAP 10 (27) 13 (36)
IPPV 24 (67) 20 (56)
FiO2 requirements 27 [23–30] 28 [23–33] 0.2
Oxygen saturations 93 [91–97] 94 [93–95] 0.8
pH 7.32 [7.29–7.38] 7.34 [7.30–7.38] 0.3
PDA diameter (mm) 3.3 [2.8–3.6] 1.7 [0.2–2.3] <0.001
Maximum pressure gradient (mm Hg) 18 [10–31] 30 [18–38] 0.002
LA:Ao 1.9 [1.7–2.2] 1.8 [1.5–2.0] 0.13
Left ventricular output (mL/kg/min) 251 [182–293] 264 [179–330] 0.13
Shortening fraction (%) 42 [37–47] 39 [32–42] 0.2
Left ventricle TDV (cm/s)
s0 4.7 [4.1–5.4] 4.2 [3.0–4.5] 0.2
e0 4.1 [3.5–5.1] 4.1 [2.8–4.8] 0.3
a0 6.4 [4.4–8.0] 4.5 [3.9–6.2] 0.2
Right ventricle TDV (cm/s)
s0 7.2 [5.9–7.6] 6.7 [5.4–8.5] 0.2
e0 7.3 [5.0–8.5] 5.6 [4.9–7.7] 0.1
a0 9.2 [8.0–12.5] 9.7 [7.6–11.7] 0.2
Abdominal aorta end diastolic flow (m/s) −0.19 [−0.28 to −0.17] 0.09 [0.05–0.17] 0.03
MCA end diastolic flow (m/s) 0 [0–0.6] 0.07 [0–0.10] 0.02
Date are presented as medians [IQR] and counts (%).
CPAP, continuous positive pressure ventilation; FiO2, fractional inspired oxygen; IPPV, invasive positive pressure ventilation; LA:Ao, left atrial to aortic root ratio; MCA, middle cerebral
artery; PDA, patent ductus arteriosus; TDV, tissue Doppler velocity.

DISCUSSION paracetamol achieved similar PDA closure rates to ibuprofen

This study demonstrates that there may be a role for intravenous
paracetamol in late closure of infants with a haemodynamically
significant PDA in order to avoid haemodynamic compromise
and subsequent ligation. The cohort in this study had large
PDAs with evidence of haemodynamic significance beyond the
2nd week of life, with the majority being ventilator dependent.
In addition to prolonged ventilation, there was a high incidence
of sepsis and NEC in this population signifying their unfavour-
able clinical course. Therefore, they are likely to be representa-
tive of infants referred for PDA ligation. The use of paracetamol
resulted in a change in PDA diameter in the majority of infants
ranging from complete closure to significant restriction with
only four infants eventually undergoing PDA ligation. The four
deaths occurring in this series cannot be attributed to paraceta-
mol administration. However, further data in a larger cohort of
infants are needed to ascertain the safety of paracetamol in
preterm infants.
Several studies have demonstrated the potential efficacy of
paracetamol in early PDA closure. Oncel et al6 were the first to
describe the efficacy of intravenous paracetamol in the early
closure of PDA when administered between 2 and 15 days of
life at a dose of 60 mg/kg/day for 3 days. In their case series of
10 infants between 24 and 29 weeks gestation, the administra-
tion of intravenous paracetamol resulted in the successful PDA
closure in all infants. More recently in a randomised controlled
trial, the same group compared the efficacy of oral paracetamol
with that of oral ibuprofen in a group of 80 preterm infants less
than 1250 g given between 48 and 72 h of age. Oral
EL-Khuffash A, et al. Arch Dis Child Fetal Neonatal Ed 2015;0:F1–F4. doi:10.1136/archdischild-2014-307930
(72.5% vs 77.5%) with no significant differences in reopening
rates.7 These two studies highlight the efficacy of paracetamol
when used early in the neonatal course. However, more studies
are needed in a larger cohort to further study its efficacy and
safety. In addition, the use of paracetamol in the late treatment
of PDA in order to avoid ligation needs further exploration.
The use of intravenous paracetamol in the late treatment of
PDA in infants who are either candidates for a PDA ligation or
those already referred for the procedure is worth further explor-
ation. The gradual closure of the PDA diameter that occurs with
the use of medical therapy may lead to a lesser physiological
impact than a sudden occlusion which occurs with ligation.
None of the infants in this series developed clinical features of
low cardiac output syndrome that occurs in up to 40% of
infants following PDA ligation. It is interesting to note that
despite potentially avoiding PDA ligation, the high incidence of
morbidity associated with the procedure (such as NEC, ROP
and CLD) was present in this cohort. This supports the recent
realisation that the association between PDA ligation and
adverse outcome is confounded by indication and the sick
nature of infants undergoing ligation.2 The infants in this
cohort were exposed to the effect of the ductal shunt for a pro-
longed period of time. Therefore, the high rate of CLD noted
in this group may be a consequence of long-term pulmonary
overcirculation. Similarly, chronic systemic hypoperfusion result-
ing from left-to-right shunting may explain the high rate of
NEC in this group as it is becoming increasingly recognised that
long-term gut hypoperfusion is a risk factor for this condition.
F3
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Short research report
Those infants are generally of very low birth weight and gesta-
tion and are therefore exposed to the potential effects of the
PDA shunt for a long period of time and, as a result, are maybe
more likely to develop those morbidities.
This study is limited by its retrospective nature and the lack
of a controlled group who did not receive paracetamol. It is
therefore feasible that some of those PDAs could have closed
spontaneously over time. The use of intravenous (and oral)
paracetamol for the late treatment of PDA should be systematic-
ally evaluated.
Contributors All the authors listed in the manuscript have made a substantial
contribution to the conception and design of the work. AEL-K wrote the first draft
and all authors revised it critically for important intellectual content. All authors have
provided final approval to the submitted manuscript and agree to be accountable for
all aspects of the work. In particular, ATJ and JS performed the echocardiograms
and measurement of echo parameters. AEL-K performed the statistical analysis and
AC collected the clinical data. OF provided the cardiology expertise and JM was the
senior author overseeing the coordination of the project.
Funding This research has received funding from the EU FP7/2007–2013 under
grant agreement no. 260777 (The HIP Trial).
Competing interests None.
F4 EL-Khuffash A, et al. Arch Dis Child Fetal Neonatal Ed 2015;0:F1–F4. doi:10.1136/archdischild-2014-307930
Ethics approval Ethical approval was obtained from the Rotunda Hospital’s and
Coombe Women and Infants University Hospital’s ethics committees.
Provenance and peer review Not commissioned; externally peer reviewed.
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2 Weisz DE, More K, McNamara PJ, et al. PDA ligation and health outcomes:
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preterm infants: understanding the physiology. J Pediatr 2013;162:1100–6.
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 Downloaded from http://fn.bmj.com/ on February 7, 2015 - Published by group.bmj.com

Late medical therapy of patent ductus

arteriosus using intravenous paracetamol
Afif EL-Khuffash, Adam T James, Aoife Cleary, Jana Semberova, Orla
Franklin and Jan Miletin

Arch Dis Child Fetal Neonatal Ed published online February 4, 2015

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