The Journal of Maternal-Fetal & Neonatal Medicine

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Efficacy and safety of oral paracetamol versus oral

ibuprofen for closure of patent ductus arteriosus
in preterm infants: a randomized controlled trial

Rania A. El-Farrash, Mohammed S. El Shimy, Abeer S. El-Sakka, Manal G.

Ahmed & Dina G. Abdel-Moez

To cite this article: Rania A. El-Farrash, Mohammed S. El Shimy, Abeer S. El-Sakka, Manal G.
Ahmed & Dina G. Abdel-Moez (2018): Efficacy and safety of oral paracetamol versus oral ibuprofen
for closure of patent ductus arteriosus in preterm infants: a randomized controlled trial, The Journal
of Maternal-Fetal & Neonatal Medicine, DOI: 10.1080/14767058.2018.1470235

To link to this article: https://doi.org/10.1080/14767058.2018.1470235

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 Efficacy and Safety of Oral Paracetamol versus Oral
Ibuprofen for closure of patent ductus arteriosus in
preterm infants: A Randomized Controlled Trial

Rania A. El-Farrash1, Mohammed S. El Shimy1, Abeer

S. El-Sakka1, Manal G. Ahmed2, Dina G. Abdel-Moez2

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1 Pediatrics Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt

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2 Neonatal intensive care unit at the maternity hospital, Ain Shams University, Cairo, Egypt

Authors
Rania Ali El-Farrash:
Highest academic degree: MD Pediatrics.
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Assistant Professor of Pediatrics, Pediatrics Department, Ain Shams University.
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Mohammed Samy El-Shimy:

Highest academic degree: MD Pediatrics.
Professor of Pediatrics, Pediatrics Department, Ain Shams University.
Abeer Salah-eldin El-Sakka:
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Highest academic degree: MD Pediatrics.

Assistant Professor of Pediatrics, Pediatrics Department, Ain Shams University.
Manal Gamal-eldin Ahmed:
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Highest academic degree: PhD

Neonatology consultant, Neonatal intensive care unit at the Maternity Hospital, Ain Shams
University.
Dina Gamal Abdel-Moez:
Highest academic degree: M.B., B.Ch.
Ministry of Health, Cairo, Egypt.

*Correspondence to:
Name : Rania Ali El-Farrash
Address : Department of Pediatrics, Faculty of Medicine, Ain Shams University, Abbassya
Square, Cairo, Egypt.
 Mobile no. : +20-122-2208550
E-mail : rania.elfarrash@med.asu.edu.eg
Running title: Oral Paracetamol vs Ibuprofen in Preterms with PDA
Keywords: Paracetamol; Ibuprofen; Patent Ductus Arteriosus; Preterm infant.
All the authors equally contributed in this article.
Contributors: All authors were involved in concept, design, data collection, analysis and
drafting of the manuscript.
Running title:Paracetamol versus Ibuprofen for PDA closure
The authors have no disclosures to declare.

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Financial disclosure: None
Competing interest: None

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Number of tables: 4
Number of figures: 1
Number of references: 23

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ABSTRACT

Objective: To evaluate the efficacy and safety of oral paracetamol versus oral ibuprofen in the treatment

of hemodynamically significant patent ductus arteriosus (hsPDA) in preterm infants. Study Design:
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An interventional randomized case-control study, registered in ClinicalTrials.gov (NCT03265782), was

conducted on 60 preterm infants with gestational age ≤ 34 weeks, postnatal age of 2-7 days and color
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Doppler echocardiographic evidence of hsPDA. Neonates were randomly assigned to 2 groups; 30

received oral ibuprofen and 30 received oral paracetamol. With failure of ductal closure, a second

course of ibuprofen or paracetamol was given. The included newborns were subjected to detailed

history, clinical examination, laboratory investigations that included complete blood count, renal and

liver function tests and echocardiographic evaluation. Results: Oral paracetamol was as effective as

ibuprofen for the closure of PDA with one course of treatment (p>0.05). Moreover, oral paracetamol

was superior to ibuprofen among neonates who needed 2nd course of treatment with significant decrease

in end diastolic flow velocity in the left pulmonary artery (0.35±0.09 vs. 0.19±0.06, p=0.014), right
ventricular systolic pressure (40.50±12.91 vs. 20.50±0.58, p=0.016) and left atrium to aortic root

ratio (1.23±0.14 vs. 1.07±0.04, p=0.046) when compared to ibuprofen group. Furthermore, the mean

difference between pre- and post- treatment PDA size was significantly higher in the paracetamol

group compared with ibuprofen group after the 2nd course of treatment (1.07±0.32 vs. 0.73±0.38,

p=0.024).Oral paracetamol was comparable to ibuprofen in terms of the rate of non-surgical ductal
closure [28 (93.3%) vs. 24 (80%), p=0.591]. In addition, oral paracetamol was as safe as oral ibuprofen

in terms of gastrointestinal perforation or bleeding, necrotizing enterocolitis, bronchopulmonary

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dysplasia, intraventricular hemorrhage, thrombocytopenia, hepatic or renal dysfunction. Conclusions:

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Oral paracetamol is an effective and well-tolerated first-line drug treatment for PDA in premature

infants.

INTRODUCTION
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Hemodynamically significant patent ductus arteriosus (hsPDA) is a common cause of morbidity
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and mortality among preterm infants, affecting more than 40% of preterm infants.[1]

Rapid and adequate treatment is necessary to prevent complications; surgical ligation is the most

effective, but invasive, treatment. Prostaglandin E2 (PGE2) plays a major role in maintaining ductal
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patency in utero in smaller and larger mammals including humans. It is the most potent vasodilator

of the ductus.[2] Anti-Prostaglandin, serves as a good alternative for non-invasive closure of PDA.
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[3]

Ibuprofen, a non-steroidal anti-inflammatory drug, inhibits both cyclooxygenase-1 and

cyclooxygenase-2, which are enzymes necessary for the conversion of arachidonic acid to various

prostaglandins among them PGE2.[2]

Unlike ibuprofen, paracetamol is thought to act on prostaglandin synthase at the peroxidase region

of the enzyme.[4] The role of paracetamol as an alternative treatment for the closure of hsPDA has

gained attention because of the potential side-effects of cyclooxygenase inhibitors.[3, 5]

The aim of this study is to compare the efficacy and safety of oral paracetamol versus oral ibuprofen

in the treatment of PDA in preterm infants.

PATIENTS AND METHODS

This double-blind, randomized controlled trial included 60 preterm infants with gestational age

≤34 weeks, postnatal age of 2-7 days and color Doppler echocardiographic evidence of PDA. The

included neonates were admitted to neonatal intensive care unit of Obstetrics and Gynecology

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Hospital, Ain Shams University during the period from June 2015 to June 2017. Patients with

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bleeding tendency, platelet count less than 60.000/mm3, urine output less than 1 ml/kg/hour,

serum creatinine concentration level more than 1.8 mg/dL, other congenital heart disease or

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any other major congenital anomalies were excluded. The mothers of the newborns under study
were informed about the purpose of the study and provided written consent. Study protocol was

approved by the Ethical Committee of Ain Shams University hospitals. This trial is registered at
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ClinicalTrials.gov; identifier: NCT03265782. Reporting of the study conforms to CONSORT 2010
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statement [6] with a checklist (Supplementary table 1).

Randomization and blinding:
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A total of 139 preterm neonates with PDA were assessed for eligibility; only 107 had

echocardiographically confirmed hsPDA and the remaining had minimal duct shunting closed

on follow up. Out of 107, 47 were excluded: 10 neonates with bleeding tendency and/or
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thrombocytopenia, 9 neonates with duct-dependent congenital heart disease, 7 neonates with other

major congenital anomalies, 3 neonates with urine output ˂1 ml/kg/hour, 4 died before treatment

start and 14 declined to participate. Sixty neonates were randomly assigned into 2 groups; Group I

included 30 preterm newborns received oral ibuprofen and Group II included 30 preterm newborns

received oral paracetamol (Figure 1).

Drug administration was carried out according to a pre-determined schedule within the

investigational drug pharmacy with allocation concealment by opaque sequentially numbered

sealed envelope. Blinding included the parents of the studied neonates, the attending neonatologist,

data collectors, outcome adjunctors and the echocardiologist.

Clinical, laboratory and radiologic assessment:

All the included newborns were subjected to detailed perinatal and family history, thorough

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clinical examination, standard neonatal care and to monitor safety of the treatment drugs, laboratory

investigations was done including complete blood count (CBC) using Sysmex XT-1800i (Sysmex,

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Kobe, Japan), measurement of serum creatinine, blood urea nitrogen (BUN), serum total and direct

bilirubin, serum alanine aminotransferase (ALT), as well as aspartate aminotransferase (AST) using

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Cobas Integra 800 analyzer (Roche Diagnostics, Mannheim, Germany). Plain X-ray chest and heart

posteroanterior view was done on admission and repeated as needed. Plain X-ray Abdomen (erect
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and supine) was done to diagnose necrotizing enterocolitis (NEC) and help differentiate its stages.
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Echocardiographic assessment:

Echocardiographic measurements were done according to the recommendations of The

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American Society of Echocardiography [7] by the same observer (M. Ahmed, PhD) using Vivid

3 Pro ultrasound scanner (GE medical systems, Milwaukee, WI, USA) with an 8-10 MHz (10S)

probe.
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It was performed initially before starting treatment with oral paracetamol or ibuprofen
and later after 3 days from starting treatment in both paracetamol and ibuprofen to establish the

structural normality of the heart as well as to estimate the ejection fraction, pulmonary artery

systolic pressure, internal diameter of the duct size, left atrium to aortic root ratio (LA:AO), left to

right shunting of blood, end diastolic reversal of blood flow in aorta.

 Shunting across the PDA was graded as mild, moderate and severe according to internal

ductal diameter (<1.5, 1.5 to 2, and >2 mm, respectively).[8]

Hemodynamically significant PDA was defined by the presence of at least one of the

following criteria:internal ductal diameter ≥ 1.5 mm; Left-atrium to- aortic-root (LA/Ao) ratio in

moderate PDA between 1.4 and 1.6 and >1.6 in large PDA; Reverse or absent diastolic flow in the
descending aorta; Left pulmonary artery diastolic flow velocity (LPA) >0.25 m/sec.[9]

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Surgical PDA ligation was considered when medical treatments of echocardiographically

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confirmed hsPDA have failed.[10]

Study drug administration:

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The enrolled neonates were randomly assigned to receive oral ibuprofen or oral paracetamol. Patients

received oral ibuprofen (Ibuprofen suspension 100 mg/5ml; Abbott, Egypt) 10 mg/kg/d for first
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day followed by 5 mg/kg/day for the next 2 days, a second course was given in the form of 5 mg/
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kg/day for 3 more days if the duct was still significantly patent. Patients received oral paracetamol

(acetaminophen suspension 250 mg/5ml; EPICO, Egypt) 15 mg/kg/6 hours for 3 successive days,

with failure of ductal closure, a second course paracetamol was given.

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Outcome measures:

Primary outcome measurements include; PDA closure after 1st course, need to give a second course
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of medication, need for surgical ligation. Secondary outcomes include neonatal mortality, early

complications that occurred in the first week of life; intraventricular hemorrhage (IVH), NEC,

gastrointestinal bleeding or perforation, renal impairment as well as hepatic affection and late

complications that occurred from the 8th day to 2nd month of life eg. bronchopulmonary dysplasia

(BPD).

Statistical Analysis:
The sample size was calculated using power and sample size calculation program EpiInfo® version

6.0. A sample size of at least 20 neonates in each group was enough to find a difference and detect
a response rate of 75% with α error= 0.05 and power of study= 80%. The analyses were conducted
based on intention-to-treat principle.

In order to compare quantitative parametric variables between two groups, Student t-test was used

while Analysis of Variance (ANOVA) with post hoc test was applied for comparison between

more than 2 groups. For qualitative data, Chi-square test and/or Fisher exact test was used. The

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comparison between two paired groups were done by using paired t-test when the data were

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parametric. A p value <0.05 was considered the cut-off value for significance in all analyses.

Analysis of data was done using Statistical Program for Social Science version 15 (SPSS Inc.,

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Chicago, IL, USA).
RESULTS

During the course of this study, 4 neonates died in ibuprofen group; 2 males of 28 weeks and 30
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gestational age died secondary to early-onset sepsis at day 9 and 12 of life respectively. 2 females,
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30 and 33 weeks gestational age died day 24 and 35 of life because of hospital acquired infection.

2 neonates died in paracetamol group; one was a male baby of 30 weeks gestational age who died

secondary pulmonary hemorrhage at day 10 of life and a 28 weeks male with 750 g birth weight
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died at day 7 of life secondary to septicemia (Figure 1).

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Baseline clinical and Echocardiographic characteristics of the studied groups showed no

significant differences between both groups (Table 1, 2). The age of start of treatment with oral

paracetamol was comparable with the age of start of oral ibuprofen (6.05±5.26 vs 7.85±5.96,

respectively, p=0.38).

Echocardiographic measurements of ibuprofen group are shown in Table 2. The mean

ductal diameter was significantly reduced after 1st course (from 2.46 ± 0.62 mm to 1.96 ± 0.57 mm,

p=0.029) and after 2nd course (1.73 ± 0.44 mm, p=0.001) with significant difference of the direction
of the shunt was noted after 1st course of treatment (p=0.022). Moreover, significant reduction of

mean LPA value was noted after the 1st course (from 0.36 ± 0.09 m/sec to 0.27 ± 0.13 m/sec, p=

0.035). RVSP was reduced after 1st course of treatment with ibuprofen (from 43.05 ± 17.79 mmHg

to 31.50 ± 11.40 mmHg, p=0.043).

Furthermore, total ductal closure was reported in 24 of 30 (80%) in premature infants given
oral ibuprofen, 12 of 30 (40%) was documented after the first course and 4 of 30 (13.3%) after

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the second course. Eight out of 30 (26.7%) were still shunting after the second course but did not

require respiratory support, or further treatment of the ductus which closed spontaneously before

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discharge. Two neonates out of 30 required surgical closure (6.7%) (Figure 1).

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Echocardiographic measurements of paracetamol group are shown in Table 2. The mean

ductal diameter was significantly reduced after 1st course (from 2.22 ± 0.58 mm to 1.41 ± 1.06

mm, p=0.014) with further significant reduction of the ductal diameter observed after 2nd course
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(1.15±0.40 mm, p<0.001). Significant difference in the direction of the shunt was noted after the 1st
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course of treatment; p=0.003, and after 2nd course; p=0.02. Moreover, significant reduction of mean

LPA value was noted after the 1st course (from 0.32 ± 0.06 m/sec to 0.24 ± 0.10 m/sec, p=0.012)

with further decrease after the 2nd course (0.19 ± 0.06 m/sec, p<0.001). RVSP value was reduced
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after 1st course of treatment with paracetamol (from 43.45 ± 11.24 mmHg to 35.80±9.07 mmHg,

p=0.049) and after the 2nd course further significant reduction was noted (20.50 ± 0.58 mmHg,
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p<0.001).

Moreover, total ductal closure was observed in 28 out of 30 (93.3%) premature infants
received oral paracetamol; 20 of 30 (66.7%) after the first course, 4 of 30 (13.3%) after the second
course and 4 of 30 (13.3%) were still shunting after the second course but did not require respiratory
support, or further treatment of the ductus which closed spontaneously before discharge and none
needed surgical ligation (Figure 1).
There was no statistically significant difference between both groups as regard ECHO findings
after of 1st course of treatment (p>0.05), while there was significant decrease in LPA (0.35±0.09 vs.
0.19±0.06, p=0.014), RVSP (40.50±12.91 vs. 20.50±0.58, p=0.016) and LA/Ao ratio (1.23±0.14
vs. 1.07±0.04, p=0.046) in the paracetamol group compared with ibuprofen group after the 2nd
course of treatment (Table 2). Furthermore, the mean difference between pre- and post- treatment
PDA size was significantly higher in the paracetamol group compared with ibuprofen group after
the 2nd course of treatment (1.07±0.32 vs. 0.73±0.38, p=0.024).

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All the studied neonates tolerated the received treatment well without side effects that could be

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attributed to drug intake; skin rash, gastritis, thrombocytopenia, hepatic or renal dysfunction, etc.

(Table 3). None of our patients developed NEC, IVH, gastrointestinal bleeding/perforation nor
renal/hepatic failure.
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As regards neonatal outcomes shown in table 4, no statistically significant difference was found
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among both groups (p>0.05). The closure rate of oral paracetamol was comparable to that of oral
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ibuprofen after the first course of the treatment (66.7% vs. 40 %, p=0.272) and after 2nd course of
treatment (80.0% vs. 66.7%, p=0.929). The total ductal non-surgical closure was comparable in
both groups (93.3% vs. 80.0%, p=0.591) with no reported ductal re-opening after closure had been
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achieved.

DISCUSSION
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In our unit, prior to this study, paracetamol was not used as the primary choice but rather as

an alternative treatment for the closure of hsPDA in cases where ibuprofen was contraindicated.

This paracetamol treatment protocol was reported for the first time in a neonate with hsPDA and

cyclooxygenase inhibitors were contraindicated [3]. Therefore, to test a hypothesis of whether

paracetamol is as effective as ibuprofen in treatment of hsPDA, we conducted this prospective,

randomized controlled trial in preterm infants with gestational age ≤ 34 weeks to compare the

efficacy and safety of oral paracetamol with ibuprofen for the pharmacologic closure of PDA.
 Our study showed that oral paracetamol and ibuprofen were similarly effective for the

closure of PDA; the closure rate of oral paracetamol was comparable to that of oral ibuprofen after
the 1st and the 2nd courses of treatment with comparable total ductal non-surgical closure between

both groups. In an additional assessment of oral paracetamol efficiency, ECHO measurements

showed significant decrease in LPA, RVSP and LA/Ao ratio in paracetamol group when compared

with ibuprofen group after the 2nd course of treatment.

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Several studies verified the efficacy of paracetamol in very low birth weight neonates [3,

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5, 11, 12, 13, 14, 15]; five of them reported a rate of ductal closure of 71-100% [3, 5, 11, 12, 15].

Concerning the safety of oral paracetamol, our results were similar to those of Oncel et al.[16],

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Allegaert et al.[17], Yurttutan et al.[18] who declared that there were no signs of hepatic or renal

intolerance during and following administration of paracetamol.

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Studies comparing oral paracetamol vs. oral ibuprofen in PDA closure reported that oral
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paracetamol and ibuprofen were similarly effective for the closure of PDA[3, 5].Also, Dang et

al.[19] published a randomized control trial comparing the efficacy of oral ibuprofen and oral

paracetamol in the treatment of hsPDA, they found that, the ductus was closed in 65 infants (81.2%)
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of the paracetamol group compared with 63 (78.8%) of the ibuprofen group with no significant

difference between the two treatments (p =0.693). After the 1st course of treatment, ductal closure
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occurred in 45 infants (56.3%) given oral paracetamol and in 38 infants (47.5%) administered oral

ibuprofen (p=0.268). After continuing to receive the assigned drug treatment, the ductus closed

in another 4 patients of each group (p=0.62). Later on, Oncel et al.[16] conducted a randomized

clinical trial and reported that, after the first course of treatment, the PDA was completely closed

in 31/40 (77.5%) of the patients assigned to the oral ibuprofen group and 29/40 (72.5%) of those

enrolled in the oral paracetamol group (p=0.6).

 Regarding the drug safety profile, oral paracetamol was as safe as oral ibuprofen in terms

of gastrointestinal perforation or bleeding, NEC, BPD, IVH, thrombocytopenia, hepatic or renal

dysfunction. Similarly, Oncel et al.[5] andDang et al.[19]reported that both drugs were tolerated

and deemed safe in terms of renal and liver variables, as well as a lack of statistically significant

difference in major complications (NEC, IVH, BPD).

As regards oral ibuprofen, there was no statistically significant difference between pre- and

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post-treatment hematological parameters in our study. However, Zecca et al.[20]; Rheinlaender et

al.[21] reported that ibuprofen seem to be associated with higher total bilirubin levels in premature

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neonates. Moreover, Su et al.[22] documented a significantly higher BUN at 24, 48, 72, 96 and 120

hours after intravenous (IV) ibuprofen administration. Also, Vieux et al.[23] observed that urine

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output was significantly decreased in the IV ibuprofen group during the first days of life (p=0.002),

differences disappeared after ibuprofen withdrawal.

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The present study had the limitation of not including a placebo control group which would
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have been more meaningful to estimate the spontaneous PDA closure rate. However, it would

have been unethical to use a placebo in such preterms with hsPDA. Also, the intervention was

not completely blinded because of the different number of doses per day of the drugs. However,
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the most important outcome—PDA closure—was made by a cardiologist who was blinded to the

treatment groups. Another limitation is the modest size of the study population. However, our
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sample size calculation and findings were indicative, allowing us to assume that paracetamol has a

potential clinical value among patients with PDA. It is possible that the inclusion of more patients
would have revealed further differences, in addition to those derived from the present analysis.

In conclusion, the current study has provided several important implications for the clinical

treatment of PDA. It demonstrated that oral paracetamol is an effective and well-tolerated, first-

line drug treatment of PDA that was comparable to ibuprofen in terms of the rate of ductal closure

and even showed decreased LPA, RVSP and LA/Ao ratio. Therefore, paracetamol may become the
choice drug for early curative closure of PDA in premature infants with the advantage of being

safe, available and cheap.

Conflict of interests

The authors declare that they have no conflict of interests.

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Figure legends

Figure (1): Consort Flow Diagram for the Enrolled Neonates

Table (1):Baseline clinical and Echocardiographic characteristics of the studied groups

 Ibuprofen group Paracetamol group test p-value
(n=30) (n=30)

GA (wks), mean ± SD 31.73±1.98 30.53±1.55 1.847 0.075

Mode of delivery, n (%) 20 (66.6) 24 (80) 0.170 0.679

CS 10 (33.3) 6 (20)
VD

Male Sex, n (%) 14 (46.7) 14 (46.7) 0.000 1.000

D
Birth weight (kg), mean ± SD 1.74 ± 0.47 1.53 ± 0.56 1.087 0.286

TE
APGAR score, mean ± SD 5.44 ± 2.90 5.93 ± 0.92 0.607 0.549
At 1 min 8.06 ± 0.77 8.14 ± 0.77 0.285 0.778
At 5 min

PPROM, n (%)

Chorioamnionitis, n (%)
10 (33.3)

10 (33.3)
EP 4 (13.3)

10 (33.3)
1.677

0.000
0.195

1.000
C
Type of oxygen support, n (%) 8 (30.77) 8 (30.77) 0.400 0.819
AC

NCPAP 16 (61.54) 14 (53.85)

CMV (IMV or SIMV) 2 (7.69) 4 (15.38)
HFV

Age Ibuprofen/Paracetamol 7.85 ± 5.96 6.05 ± 5.26 0.877 0.388

ST

started (days), mean ± SD

Severity of the PDA shunt, n(%), 16 (53.3) 14 (46.7) 0.000 1.000

JU

Moderate (IDD 1.5-2 mm) 14 (46.7) 16 (53.3)

Severe (IDD >2 mm)

CMV: conventional mechanical ventilation; CS: Caesarean section; GA: gestational age; kg: kilogram; HFV: high
frequency ventilation; IDD: internal ductal diameter; IMV: intermittent mandatory ventilation; LA/Ao: left atrium to
aortic root ratio; LPA: end diastolic flow velocity in the left pulmonary artery; mm: millimeter; m/sec: meter per second;
mmHg: millimeter mercury; n: number; min: minute; NCPAP: nasal continuous positive airway pressure; PDA: patent
ductus arteriosus; PPROM: preterm premature rapture of membrane; RD: reversed diastole RVSP: right ventricular
systolic pressure; SD: standard deviation; VD: vaginal delivery; wks: weeks.
 Data were expressed as mean ± SD where Student-t test was applied for comparisons or as number and percentage
using Chi-square (X2) test for comparison.

Table (2): Echocardiographic measurements before, after 1st and 2nd course of ibuprofen/
paracetamol

Ibuprofen group Paracetamol group p1 p2 p3

Pre- After After *p- Pre- After After *p-

treatment 1st 2nd valuetreatment 1st 2nd value

D
(n=30) course course (n=30) course course
(n=30) (n=18) (n=30) (n=10)

TE
Shunt Direction, 28 16 14 0.088 26 6 (20) 4 (40.0) 0.0020.6650.0990.238
n (%), (93.33) (53.33) (77.8) (86.66) 0 (0.00) 0 (0.00)
Left to right 2 (6.66) 2 (6.67) 0 (0.00) 0 (0) 4 2 (20.0)
Right to left
Bidirectional
Closed
0 (0) 0 (0.00) 0 (0.00)
0 (0) 12 (40) 4 (22.2)
4
(13.33)
0 (0) EP (13.33)
20
(66.67)
4 (40.0)
C
PDA size (mm), 2.46 1.96±0.571.73±0.440.0092.22±0.581.41±1.061.15±0.400.0040.2230.0870.066
mean ± SD ± 0.62
AC

LPA (m/sec), 0.36 0.27±0.130.35±0.090.0250.32±0.060.24±0.100.19±0.060.0040.1510.5510.014

mean ± SD ± 0.09

Reversed 10 4 4 (22.2) 0.457 2 (6.66) 2 (6.67) 2 (20.0) 0.6150.0931.0000.560

ST

diastole, n (%) (33.33) (13.33) 14 28 28 8 (80.0)

Yes 18 (60) 26 (77.8) (93.33) (93.33) 0 (0.00)
No 2 (6.66) (86.67) 0 (0.0) 0 (0) 0 (0.00)
Absent diastole 0 (0.00)
JU

RVSP (mmHg), 43.05±7.7931.50±1.40

40.50±12.91
0.04143.45±1.24
35.80±0.07 <0.0010.9330.2690.016
20.50±0.58
mean ± SD

LA/Ao ratio, 1.14±0.401.16±0.121.23±0.140.7231.14±0.151.09±0.121.07±0.040.4410.9750.0980.046

mean ± SD

LA/Ao: left atrium to aortic root ratio; LPA: end diastolic flow velocity in the left pulmonary artery; m/sec: meter per second;
mmHg: millimeter mercury n: number; PDA: patent ductus arteriosus; RVSP: right ventricular systolic pressure; SD: standard
deviation.
*Data were expressed as mean±SD where one-way ANOVA test was applied for comparisons, or numbers and percentages were
Chi-square (X2) test was used.

p1: pre-treatment echocardiographic measurements of both groups, p2: echocardiographic measurements of both groups after 1st
course of ibuprofen/paracetamol, p3: echocardiographic measurements of both groups after 2nd course of ibuprofen/paracetamol.
Data were expressed as mean±SD where Student-t test was applied or as number and percentage where Chi-square (X2) test was
used for comparisons between both groups.

Table (3):Hematological, renal and hepatic characteristics of the 2 studied groups

D
TE
EP
C
AC
ST
JU
 Ibuprofen group Paracetamol group *p-
value
Pre-treatment Post-treatment p- Pre-treatment Post-treatment p-value
value

TLC (×103/ 16.25 ± 6.42 16.34 ± 4.46 0.97 19.15 ± 6.13 15.29 ± 5.07 0.07 0.57
uL)

Hb (g/dL) 12.56 ± 2.35 13.36 ± 1.78 0.21 14.13 ± 2.59 13.48 ± 1.81 0.46 0.86

D
HCT (%) 41.08 ± 6.44 43.70 0.22 45.30 ± 7.77 43.41 ± 6.12 0.52 0.89
± 4.65

TE
PLT (×103/ 43.70 310.77 0.83 311.73 262.80 0.29 0.25
uL) ± 4.65 ± 67.88 ± 119.26 ± 130.91

BUN
dL)
(mg/ 22.31 ± 7.11 18.92
± 6.69
0.17
EP
21.40 ± 6.12 17.87 ± 6.86 0.15 0.68
C
S.Cr (mg/ 0.57 ± 0.17 0.45 ± 0.18 0.07 0.49 ± 0.18 0.40 ± 0.20 0.21 0.50
dL)
AC

ALT (IU/L) 12.92 ± 9.07 15.31 0.44 13.20 ± 3.93 13.20 ± 5.52 1.00 0.42
± 7.92
ST

AST (IU/L) 37.08 50.08 0.26 30.73 37.27 ± 9.41 0.08 0.16
± 28.26
± 33.17 ± 10.13

Total 8.83 ± 3.26 6.55 ± 3.35 0.07 9.31 ± 2.10 9.01 ± 3.36 0.49 0.21
JU

bilirubin (mg/
dL)

D. bilirubin 1.15 ± 0.63 0.93 ± 0.57 0.15 1.01 ± 0.47 1.11 ± 0.40 0.42 0.35
(mg/dL)

Urine 2.92 ± 0.97 2.26 ± 1.03 0.07 2.93 ± 0.93 2.66 ± 0.79 0.42 0.242
output (mg/
kg/hr)
ALT: alanine aminotransferase; AST: aspartate aminotransferase; BUN: blood urea nitrogen; D. bilirubin: direct
bilirubin; dL: deciliter; g: gram; HCT: Hematocrit; Hb: Hemoglobin; hr: hour; IU: International unit; kg: kilogram; L:
Liter; mg: milligram; n: number; PLT: Platelets; S.Cr: Serum creatinine; SD: standard deviation; TLC: total leucocytic
count.

Data were expressed as mean ± SD where paired-t test was applied for comparisons.
*P value for comparison between post-treatment levels between both groups.

D
TE
EP
Table (4): Neonatal outcomes of the 2 studied groups
C
AC
ST
JU
 Ibuprofen Paracetamol test p-value
group group
(n=30) (n=30)

Closure of PDA after 1st course of treatment, 12 (40) 20 (66.66) 1.205 0.272
n (%)

Closure of PDA after 2nd course of treatment, 0.008 0.929

n (%) 12/18 (66.6) 8/10 (80)

D
Total Ductal non-surgical closure,n (%) 24 (80.0) 28 (93.3) 0.288 0.591

TE
Ductal Surgical closure, n (%) 2 (14.29) 0 (0) 0.212 0.646

Duration of NCPAP (days), median (IQR) 17.5 (5-30) 9.5 (7-18) 0.333 0.739

Duration of MV (days),median (IQR)

Duration of hospital stay (days),median (IQR) EP 11 (8-16)

25 (14-42)
10 (8-11)

33 (20-44)
0.357

1225
0.721

0.233
C
*Bronchopulmonary dysplasia, n (%) 2 (6.67) 2 (6.67) 0.000 1.000
AC

Death, n (%) 4 (13.33) 2 (6.66) 0.000 1.000

ST

*Bronchopulmonary dysplasia was defined as oxygen requirement at postmenstrual 36th week

or discharge, whichever comes first. IQR: interquartile ranges; MV: mechanical ventilation; n:
number; NCPAP: nasal continuous positive airway pressure; PDA: Patent Ductus Arteriosus.
Data were expressed as median (IQR) where Mann-Whitney test was applied for comparisons or
JU

numbers and percentages using Chi-square (X2) test.

Table (1):Baseline clinical and Echocardiographic characteristics of the studied groups

D
TE
EP
C
AC
ST
JU
 Ibuprofen group Paracetamol group test p-value
(n=30) (n=30)

GA (wks), mean ± SD 31.73±1.98 30.53±1.55 1.847 0.075

Mode of delivery, n (%) 20 (66.6) 24 (80) 0.170 0.679

CS 10 (33.3) 6 (20)
VD

Male Sex, n (%) 14 (46.7) 14 (46.7) 0.000 1.000

D
Birth weight (kg), mean ± SD 1.74 ± 0.47 1.53 ± 0.56 1.087 0.286

TE
APGAR score, mean ± SD 5.44 ± 2.90 5.93 ± 0.92 0.607 0.549
At 1 min 8.06 ± 0.77 8.14 ± 0.77 0.285 0.778
At 5 min

PPROM, n (%)

Chorioamnionitis, n (%)
10 (33.3)

10 (33.3)
EP 4 (13.3)

10 (33.3)
1.677

0.000
0.195

1.000
C
Type of oxygen support, n (%) 8 (30.77) 8 (30.77) 0.400 0.819
AC

NCPAP 16 (61.54) 14 (53.85)

CMV (IMV or SIMV) 2 (7.69) 4 (15.38)
HFV

Age Ibuprofen/Paracetamol 7.85 ± 5.96 6.05 ± 5.26 0.877 0.388

ST

started (days), mean ± SD

Severity of the PDA shunt, n(%), 16 (53.3) 14 (46.7) 0.000 1.000

JU

Moderate (IDD 1.5-2 mm) 14 (46.7) 16 (53.3)

Severe (IDD >2 mm)

CMV: conventional mechanical ventilation; CS: Caesarean section; GA: gestational age; kg: kilogram; HFV: high
frequency ventilation; IDD: internal ductal diameter; IMV: intermittent mandatory ventilation; LA/Ao: left atrium to
aortic root ratio; LPA: end diastolic flow velocity in the left pulmonary artery; mm: millimeter; m/sec: meter per second;
mmHg: millimeter mercury; n: number; min: minute; NCPAP: nasal continuous positive airway pressure; PDA: patent
ductus arteriosus; PPROM: preterm premature rapture of membrane; RD: reversed diastole RVSP: right ventricular
systolic pressure; SD: standard deviation; VD: vaginal delivery; wks: weeks.
 Data were expressed as mean ± SD where Student-t test was applied for comparisons or as number and percentage
using Chi-square (X2) test for comparison.

Table (2): Echocardiographic measurements before, after 1st and 2nd course of ibuprofen/
paracetamol

Ibuprofen group Paracetamol group p1 p2 p3

Pre- After After *p- Pre- After After *p-

treatment 1st 2nd valuetreatment 1st 2nd value

D
(n=30) course course (n=30) course course
(n=30) (n=18) (n=30) (n=10)

TE
Shunt Direction, 28 16 14 0.088 26 6 (20) 4 (40.0) 0.0020.6650.0990.238
n (%), (93.33) (53.33) (77.8) (86.66) 0 (0.00) 0 (0.00)
Left to right 2 (6.66) 2 (6.67) 0 (0.00) 0 (0) 4 2 (20.0)
Right to left
Bidirectional
Closed
0 (0) 0 (0.00) 0 (0.00)
0 (0) 12 (40) 4 (22.2)
4
(13.33)
0 (0) EP (13.33)
20
(66.67)
4 (40.0)
C
PDA size (mm), 2.46 1.96±0.571.73±0.440.0092.22±0.581.41±1.061.15±0.400.0040.2230.0870.066
mean ± SD ± 0.62
AC

LPA (m/sec), 0.36 0.27±0.130.35±0.090.0250.32±0.060.24±0.100.19±0.060.0040.1510.5510.014

mean ± SD ± 0.09

Reversed 10 4 4 (22.2) 0.457 2 (6.66) 2 (6.67) 2 (20.0) 0.6150.0931.0000.560

ST

diastole, n (%) (33.33) (13.33) 14 28 28 8 (80.0)

Yes 18 (60) 26 (77.8) (93.33) (93.33) 0 (0.00)
No 2 (6.66) (86.67) 0 (0.0) 0 (0) 0 (0.00)
Absent diastole 0 (0.00)
JU

RVSP (mmHg), 43.05±7.7931.50±1.40

40.50±12.91
0.04143.45±1.24
35.80±0.07 <0.0010.9330.2690.016
20.50±0.58
mean ± SD

LA/Ao ratio, 1.14±0.401.16±0.121.23±0.140.7231.14±0.151.09±0.121.07±0.040.4410.9750.0980.046

mean ± SD

LA/Ao: left atrium to aortic root ratio; LPA: end diastolic flow velocity in the left pulmonary artery; m/sec: meter per second;
mmHg: millimeter mercury n: number; PDA: patent ductus arteriosus; RVSP: right ventricular systolic pressure; SD: standard
deviation.
*Data were expressed as mean±SD where one-way ANOVA test was applied for comparisons, or numbers and percentages were
Chi-square (X2) test was used.

p1: pre-treatment echocardiographic measurements of both groups, p2: echocardiographic measurements of both groups after 1st
course of ibuprofen/paracetamol, p3: echocardiographic measurements of both groups after 2nd course of ibuprofen/paracetamol.
Data were expressed as mean±SD where Student-t test was applied or as number and percentage where Chi-square (X2) test was
used for comparisons between both groups.

D
TE
EP
C
AC
ST
JU
JU
ST
AC
C
EP
TE
D