Paracetamol for Patent Ductus Arteriosus in Preterm or Term
Infants
Herlina Dimiati
1*
, Dora Darussalam
2
and Isra Firmansyah
2
1
Pediatric Cardiology Division, Department of Pediatric, Syiah Kuala University/Zainoel Abidin Hospital, Banda Aceh,
Indonesia
2
Neonatology Division,
Department of Pediatric, Syiah Kuala University/Zainoel Abidin Hospital, Banda Aceh, Indonesia
Keywords: Paracetamol, Effective Option, Patent Ductus Arteriosus
Abstract: The aim of this study was to present our experience with intravenous paracetamol for closing of PDA in
neonates contraindicated to ibuprofen or ibuprophen had failed and no candidates for surgical ligation. We
conducted study in the Neonatal Intensive Care Unit (NICU) Dr. Zainoel Abidin Hospital and Harapan
Bunda Hospital in Banda Aceh, from January to December 2017 with hemodynamic significant PDA
(hsPDA). All the subject received 15 mg/kg/6 h intravenous paracetamol for 3 days for ductal closure, and
evaluation ductal with echocardiography on the 5
th
day after the regiment. Seventy-two (72) neonates were
diagnosed of hsPDA, mean gestational age (GA) of 34.26 weeks and mean birth weight of 1945.69
grams, female babies were 39 (54.2%) and male babies were 33 (45.8%). Preterm babies were 45 (62.5%)
and full-term babies were 27 (37.5%). Twenty- six (36.1%%) babies had closed PDAs on the 5
th
days
evaluation, 11 babies (15.3%) had twice regiment , closed PDA at the 10
th
days evaluation, and 35
babies (48.6%) had more closed PDA after three or four regiment. Successful closure on paracetamol
was achieved in 51 babies (70.8%). And 21 (29.2%) had failed PDA closure. Paracetamol is an effective
option in closure PDA and should be a first-line therapeutic option when there are contraindications for
ibuprofen.
1 INTRODUCTION
Ductus Arteriosus (DA) is a heart problem that is
frequently noted in the first few weeks or months
after birth. It is characterized by the persistence of a
normal fetal connection between the aorta and the
pulmonary artery which allows oxygen-rich (red)
blood that should go to the body to recirculate
through the lungs. Closure of ductus arteriosus after
birth is very important for circulation adaptation to
the extra-uterine life. In healthy full-term newborns
DA generally undergoes functional closure between
24 and 72 hours of life (Anngreni et al., 2014).
Prolonged condition of PDA in preterms can be
associated with important complications, such as
severe respiratory distress syndrome (RDS),
prolonged need for assisted ventilation, pulmonary
hemorrhage, bronchopulmonary dysplasia (BDP),
necrotizing enterocolitis (NEC), renal function
damage, intra-ventricular hemorrhage (IVH),
periventricular leukomalacia (PLV), To prevent such
complications, the practice of DA closure is
common and it is performed at first
pharmacologically, but, in case of drugs failure or
contraindication, with surgical (Anggreni et al.,
2014; Allegaert et al., 2013; Brunner et al., 2013).
Despite years of researches and clinical
experience on PDA management, many unresolved
issues about its evaluation and treatment, with
consequent heterogeneity of clinical practices in
different centers, still remain, particularly regarding
timing and modality of intervention. In fact, the
available strategies vary from prophylactic
treatment to early or delayed therapy.
Pharmacological closure with non-steroidal anti-
inflammatory drugs (NSAIDs), mainly ibuprofen
and indomethacin, is currently the standard of care
for PDA closure in preterm infants.. However,
NSAIDs are not effective in around 25-30% of
patients and they can have side effects such as
transient renal function impairment, diminished
platelet aggregation, hyperbilirubinemia, and
gastrointestinal bleeding and perforation (Allegaert
et al., 2013; Brunner et al., 2013).
Recently, there is
Dimiati, H., Darussalam, D. and Firmansyah, I.
Paracetamol for Patent Ductus Arteriosus in Preter m or Term Infants.
DOI: 10.5220/0008792202230227
In Proceedings of the 2nd Syiah Kuala International Conference on Medicine and Health Sciences (SKIC-MHS 2018), pages 223-227
ISBN: 978-989-758-438-1
Copyright
c
2020 by SCITEPRESS – Science and Technology Publications, Lda. All rights reser ved
223
a growing interest in paracetamol for PDA closure
and it has been suggested as an alternative drug to
treat PDA. Finding the optimal pharmacological
treatment for PDA closure in very low birth weght
(VLBW) continues to remain challenging .
.
The role
of paracetamol, an inhibitor of the peroxidase
component of prostaglandin-H2 synthetase, has
been proposed for the treatment of PDA (Brunner et
al., 2013; Weisz et al., 2014).
Hammerman et al. reported for the first time
the use of paracetamol for closing of PDA
(Hammerman C et al., 2011) Since then, many
studies have reported similar efficiency of
paracetamol to cyclooxygenase (COX) inhibitors for
closing PDA and less adverse events (Dani et al.,
2016). The large number of study reported the
alternative treatment for closed the ductus (Dani et
al., 2016; El-Khuffash et al., 2014; Oncel et al.,
2013).
Since 2014, paracetamol is a standard
practice used at Dr. Zainoel Abidin Hospital and
Harapan Bunda Hospital for closure of PDA and has
been found in standard operational procedures at
Neonatal Intensive Care Unit, so there have been no
studies on the effectiveness of the drug in PDA
closure. So, the aim of this study was to present our
experience with Paracetamol intravenous (IV) for
closing PDA in preterm neonates or mature
neonates presenting contraindication to ibuprofen or
ibuprofen had failed and had feeding intolerance.
2 METHODS
This study took place in two hospital in Banda
Aceh , i.e., dr Zainoel Abidin Hospital and Harapan
Bunda Hospital. It was conducted from January to
December 2017.Subject who met inclusion criteria
were performed echocardiography, with
hemodynamically significant of PDA (hsPDA),
Echocardiography criteria of hsPDA were a ductal
diameter ≥1.5 mm, a left atrium to aortic root ratio
>1.5, and diastolic aortic retrograde flow.
Bidimensional color Doppler echocardiography with
GE Vivid Healthcare multi-frequency 7 MHz sector
probe was used. All of the babies received
paracetamol 15 mg/kg iv administration every 6 h
for 3 consecutive days, reevaluation close of PDA
done on day 5
th
. If ductus closure was confirmed by
echocardiography, treatment was discontinued, and
if PDA not closed , the regiment can be repeated
with the same dose for 3 consecutive days too.
Repetition like this regiment can only be done for 4
times. The categorized fail of PDA closed is
repetition to 4 times regiment PDA not close.
Demographic features ( gestational age/GA,
gender, birth weight, height, Apgar score, delivery
mode, antenatal steroids, MgSO4, age
treatment/days of treatment, primary reason to use
paracetamol, main outcome, adverse events, surgery,
and invasive ventilation), times of treatment,
response to treatment. Before and 24 hours after the
end of paracetamol treatment, liver function tests
were performed in all patients. In all cases, a written
informed consent was obtained.
Data were analyzed using the Statistical
Package for the Social Sciences (SPSS). A
descriptive analysis was done to elaborate subject
demographics and clinical data. A p-value of 0.05
was used to determine significant association.
3 RESULTS
Between January and December 2017 , there were
total of 72 preterm and full term babies who had
hsPDA. with range gestational age (GA) 28, and 40
weeks. (mean 34.26 weeks)., the mean birth weight
(BW) was 1945.69 g ranging from 870 to 4000 g.
The fourty five (62.5%) babies were pre-term and
the 27 (37.5%) were full term babies. Table 1
describes demographic characteristic among babies
whose received paracetamol IV
In all patients, due to feeding- intolerance and
clinic instability, iv paracetamol was started after
obtaining informed consent signature. Complete
closure was observed in 51 babies (70.8%). Of the
27 term – babies, the success of the closure of PDA
was mor3 50% (15 babies). The mean postnatal age
at the first iv paracetamol dose was 2.7 days,
ranging from 1 to 4 days.
Bivariate analysis of closed the ductal and
GA, BW, diameter PDA, days of treatment and
times regiment had significant associations (Table
2).
SKIC-MHS 2018 - The 2nd Syiah Kuala International Conference on Medicine and Health Sciences
224
Table 1: Characteristics of Subjects
Characteristics
Preterm
babies
N (%)
Term
Babies
N(%)
Sex
Girls
26
(57.8)
13 (48.1)
Boys
19
(42.2)
14 (51.9)
Mean Gestational age
32.3
37.5
(GA/weeks)
Mean Birth Weight
1.022
1.666
(BW/grams)
Mean size of PDA
(mm)
5.92
8.28
Mean days of
treatment
3
2,14
Regiment
One time
22
(48.9)
4 (14.8)
Twice
8 (17.8)
3 (11.1)
Three times
3 (6.7)
5 (18.5)
Four times
12
(26.7)
15 (55.6)
Close of PDA
36 (80)
15 (55.6)
Fail Close of PDA
9 (20)
12 (44.4)
Table 2: Bivariate analysis of close PDA in relation to
GA, BW, size of PDA, days of treatment, and times
regiment.
Variable
P Values
GA
0,015
BW
0,002
Size of PDA
0,020
Days treatment
0,001
Times regiment
0,000
GA: Gestational age, BW: Birth Weight
Tabel 3. Multivariate analysis of variable to predict close
of PDA
R
GA
2,840
BW
3,650
Size of PDA
2,740
Days of treatment
3,930
Times regiment
6,170
GA: Gestational age, BW: Birth Weight
4 DISCUSSION
More recently, oral or iv administration of
paracetamol (acetaminophen) gained attention in
PDA treatment. How paracetamol acts for closing
PDA still remains unclear, but it is known that it
inhibits prostaglandin synthetase (Weisz et al.,
2014; Hammerman et al., 2011; Dani et al., 2016).
The role of paracetamol as an alternative treatment
for closure of hsPDA has gained attention in recent
years because of its superior safety profile in
comparison to the cyclooxygenase inhibitors.
Alternatively, paracetamol has been proposed to
selectively inhibit a central isoform of COX3, but
the existence of a functional human COX3 has been
questioned (Hammerman et al., 2011; Dani et al.,
2016; El-Khuffash et al., 2014; Oncel et al., 2013).
The paracetamol also inhibits prostaglandin
synthetase activity. Although its precise mechanism
of action remains controversial. Theoretically, these
differences would permit peroxidase inhibition to be
optimally effective under conditions in which
cyclooxygenase inhibition is less active or
hypothetically, render it ideally suited for treatment
in the PDA environment (Dani et al., 2016; El-
Khuffash et al., 2014; Oncel et al., 2013; Oncel,
Uras et al., 2013; Sinha et al., 2013).
Hammerman et al. reported for the first time
several case reports on premature infants who
received paracetamol achieving ductal closure
(Hammerman et al., 2011). Since then, 24 case
reports series have been reported and 6 randomized
control trials (RCTs) showing paracetamol utility for
ductal closure with similar results comparing to
ibuprofen/indomethacin and fewer adverse events
Paracetamol for Patent Ductus Arteriosus in Preterm or Term Infants
225
(Anggreni et al., 2014; Hammerman et al., 2011).
Study by Oncel et al. used paracetamol in 10
premature infants under than 30 weeks of GA with
a 100% of effectiveness. Nevertheless, other authors
did not achieve same striking results (El-Khuffash et
al., 2014; Oncel et al., 2013). The most common
dosage is 15 mg/k/dose/6qh.. Sinha R et al , used
oral paracetamol but the result to closed ductal not
satisfying
(Sinha et al., 2013). In our study, all of the
babies had problems feeding, therefore,
paracetamol is given intravenously 15
mg/k/dose/q6h. We have reported a lower average
ductal closure probably in our study do not
separated between babies preterm and full term
babies. No studies have reported the effectiveness
of paracetamol for closure of PDA. Roofthooft DW
et al study and Tekgündüz KS et al study did not
show satisfactory results closed the ductal of
paracetamol administration (Roofthooft et al., 2013;
Tekgündüz et al., 2015). A recent report has
reinforced the long-term neurodevelopmental
safety of paracetamol in comparison to ibuprofen in
80 preterm neonates (Oncel et al., 2017).
Considering the equivocal reports published until
now and the promise offered by paracetamol as a
safer alternative, this randomized, active controlled,
masked, non-inferiority trial was planned. In our
study, no subject had the neurodevelopmental
problem after 6 month evaluation.
In our study all the neonates with hsPDA
received treatment with intravenous paracetamol
because this treatment was included in the standard
operating procedures at the NICU. The result of our
study show that there are many cases fail to close
the PDA in full term babies compared with preterm
babies (12 babies/44.4%). There are several reasons
why PDA becomes unresponsive to the
administration of Non-Steroidal Anti-Inflammatory
Drug’s (NSAIDs). The inflammatory process in the
wall of a DA occurs soon after birth. It is associated
with the influx of monocytes or macrophages into
the walls of the DA witch later induces the
prostaglandin and Nitrid-Oxcides (NO)- independent
cytokines-mediated vasodilation (Hermes-DeSantis
et al., 2006).
In preterm babies get very fantastic results
with the success of PDA closure at 36 (80%), out of
these, 22 babies (48,9%) only got one regiment
while in the term babies the success of PDA closure
in 15 babies (55,6%) received four times regiment.
These result concluded that although paracetamol
can affect the closure PDA in term babies, this
drugs far more successful in preterm subjects.
The success of PDA closure also depends on
the baby’s weight, gestational age, size of PDA and
on the day of administration drug. The small sample
size is a limitation for our study, the single adverse
event we noticed was a transient elevation in liver
enzymes and not need medicine for this condition.
Our patients had oral feeding intolerance, so
we use iv route. In our opinion, the oral route
probably does not represent the optimal choice our
subject. In these patients, gut immaturity together
with oral feeding - intolerance can lead to
unpredictable and possibly too low intestinal drug
absorption.
The single adverse event we noticed was a
transient elevation in liver enzymes in four pre-term
babies as previously has been reported in
literature, and they required no treatment.
5 CONCLUSIONS
Our results highlight that paracetamol could be
come not only an alternative treatment in closing
PDA but also the treatment of choice in several
scenarios.in term babies. Nevertheless, one of the
main limitations of this study is that it is with fewer
subjects. studies are needed to know long-term
consequences of using paracetamol for closing PDA
and to answer important questions about the optimal
dose, the best route of administration, safety and the
implications in term babies.
CONFLICT OF INTEREST
The authors declare that the research was conducted
in the absence of any commercial or financial
relationships that could be construed as a potential
conflict of interest.
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