he ductus arteriosus closes over the first few
days of life in most newborns. In preterm infants, it may remain open
even after 4-7 days of life leading to increased shunting of blood into
the pulmonary circulation and potentially compromising circulation to
systemic organs. This assumption is the keystone on which the decision
to close the patent ductus arteriosus (PDA) in a preterm baby rests.
Though spontaneous closure of the ductus is the norm
in term newborns, two-thirds of very low birth weight (VLBW) babies have
spontaneous closure in the first seven days of life and only 30% of
extremely low birth weight (ELBW) close their ductus during the neonatal
period [1]. A PDA in a VLBW baby is associated (though not causal) with
adverse outcomes like broncho-pulmonary dysplasia (BPD),
intraventricular haemorrhage (IVH), necrotizing enterocolitis (NEC) and
death [2]. However, trials have not shown any definite change in these
outcomes by treating a PDA. Treatment of PDA thus remains one of the
most debated topics in neonatal medicine with no consensus on whether to
treat, and when and how to treat! Nick Evans aptly calls it a
"conundrum" [2-4]. Be that as it may, most neonatologists would prefer
to attempt ductal closure in preterm neonates with symptoms or in those
on respiratory support.
Hemodynamic significance of PDA in clinical practice
is determined by echocardiographic assessment of size of PDA and its
association with clinical signs – mainly respiratory. Closure is
attained either pharmacologically (with prostaglandin inhibitors) or
surgically. In the year 1976, indomethacin was first used to treat PDA
in a preterm neonate [5]. After that, ibuprofen came into use. A
Cochrane meta-analysis comparing these two stated that ibuprofen was as
effective as indomethacin in closing a PDA with lesser risk of NEC or
transient renal insufficiency, thus being the drug of choice [6].
Hammerman, et al. [7] in 2009, first described the successful use
of oral paracetamol for ductal closure in a case series of 5 preterm
babies who either had contra-indications to or failed closure with
indomethacin.
Paracetamol acts mainly by inhibiting peroxidase
enzyme activity. It is a weak inhibitor of cyclo-oxygenase enzyme.
Because of the ease of availability, lesser cost and wider margin of
safety, paracetamol has generated interest among neonatologists as a
potential first line drug for ductal closure. There have been two recent
randomized controlled trails (RCTs) which have looked at efficacy of
paracetamol as first line drug for closure of hemodynamically
significant PDA in comparison to ibuprofen [8,9]. A meta-analysis of
these trials opined that paracetamol was as effective as oral ibuprofen.
A cautionary note was introduced in view of animal studies suggesting
adverse effects on developing brain after use of paracetamol. Thus the
author advised that long-term neurological outcomes should be looked at
regarding use of paracetamol in newborn [10].
In this issue, Dash, et al. [11] have
published a RCT comparing oral paracetamol with intravenous indo-methacin
with the primary outcome being closure of the PDA at 7 days. This is the
first RCT that has compared oral paracetamol with indomethacin. The
authors randomized 77 VLBW preterms having a PDA (diagnosis based on
echocardiographic findings) within 48 hours of life to receive either
paracetamol or indomethacin. PDA closure rates were 100% and 94.6% in
the paracetamol and indomethacin groups, respectively. There were no
differences in secondary outcomes such as need for surgical closure of
PDA, gastrointestinal bleed, necrotizing enterocolitis, hepatotoxicity,
hypothermia, renal dysfunction or mortality between the two groups. The
authors have rightly pointed out that the study was underpowered to
demonstrate the anticipated difference of efficacy between the two
intervention drugs. As the study recruited neonates in the first 48
hours of life, some of these neonates might have had spontaneous closure
of PDA. Even with these limitations, this study will definitely add to
the existing evidence on use of paracetamol in therapy for PDA.
Paracetamol can be used cautiously as the first line
drug in the absence of indomethacin/ibuprofen or when these drugs are
contraindicated. Larger studies comparing paracetamol versus
indomethacin/ibuprofen in symptomatic PDA may be needed before
paracetamol can be accepted as the first line drug in treatment of PDA.
It would be worthwhile to also follow-up this cohort to see the neuro-developmental
outcomes, and the same should be applicable to future RCTs using
paracetamol for closure of PDA.
Funding: None; Competing interest: None
stated.
References
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