Patent ductus arteriosus (PDA) – persistence of
the fetal ductus arteriosus – is the most common form of congenital
cardiac abnormality in newborns, with a reported frequency of 31% in
very low birth weight (VLBW) infants [1,2]. PDA is associated with
significant hemodynamic abnormalities and has varying influence in
pulmonary function. Incidence and severity of complications of PDA vary
in different subgroups of the VLBW population. Therapeutic interventions
for PDA have significant complications. If PDA is left untreated in
preterm infants, there is a high likelihood of spontaneous closure. The
purpose of this review is to assess current evidence to delineate the
group of VLBW infants who need intervention and mode of intervention.
When is PDA Considered Significant?
Despite an obvious need, no specific clinical or
echocardiographic criteria have been developed on which treatment of PDA
could be based. Possibilities for assessing ductal significance include
clinical and echocardiographic methods, and possibly biochemical
markers.
Significant PDA may be indicated by clinical signs
such as blood-stained endotracheal aspirates indicating pulmonary edema,
bounding pulses with widened pulse pressure, hyperdynamic precordium and
a continuous murmur on auscultation. Assessment is also assisted by a
radiological finding of cardiomegaly and pulmonary congestion. However,
all these signs have their own limitations, and studies have shown a
poor correlation between physical signs and the presence of PDA in the
first week of life [3].
Several echocardiographic findings are used as
surrogate markers of ductal significance [4]. Although this approach has
limitations such as inter- and intra- observer variations in
measurement, a bedside functional echocardiography gives valuable
information in assessing ductal significance. The commonly used
echocardiographic markers are: a left atrium to aortic root dimension
ratio of more than 1:1.4, a ductal diameter of more than 1.4 mm/kg body
weight, left ventricular enlargement, and diastolic flow reversal [5].
However, there are no strict criteria or scoring systems to assess the
significance of ducts and that is another area of potential research.
Published evidence indicates that B-type natriuretic peptide (BNP) and
N-terminal Pro-BNP could be used as a potential biochemical marker in
assessing the severity of ductal shunt [6].
When Does PDA Require Intervention?
The main argument in favor of treating PDA is effect
on various organ systems due to altered hemodyanamics. Left-to-right
shunting increases with the postnatal decrease in pulmonary vascular
resistance, leading to a compensatory increase in cardiac output and a
widening of the pulse pressure. The flow pattern in the aorta changes
with the development of diastolic steal. Retrograde diastolic flow may
develop in the cerebral circulation, the descending aorta, and renal and
mesenteric blood vessels. This hemodyanamic effect is presumed to cause
significant morbidities in cardiovascular and other organ systems in
preterm infants [7-14].
The main argument against active intervention in PDA
is significant adverse effects related to both medical and surgical
treatments. None of the treatment trials were designed to determine
these effects, so clinicians have had to rely on information from
prophylactic treatment trials to reach a conclusion on this issue.
Prophylactic trials using indomethacin showed transient alteration in
renal function and urine output, though this is less of a concern with
ibuprofen. Indomethacin by itself does not appear to increase the
incidence of other neonatal morbidities such as necrotizing
enterocolitis (NEC), gut perforation, retinopathy of prematurity (ROP),
chronic lung disease (CLD) or cerebral white matter injury [15].
However, an increased incidence of gut perforation has been observed
with concurrent use of indomethacin and steroids [12,16]. Although the
cerebral vasoconstrictive effect of indomethacin has been a concern for
clinicians, long-term follow up of infants who received indomethacin
prophylactically shows a decrease in the incidence of periventicular
leukomalacia (PVL) without any adverse neurodevelopmental effect at 18
months of age [17,18].
Surgical ligation of PDA is associated with its own
set of morbidities, with the potential for serious implications for
long-term outcome. The immediate morbidities associated with ligation
are pneumothorax, chylothorax, infection, vocal cord paralysis, need for
thoracotomy, and the post-ligation need for ionotropic support [19].
Surgical ligation of PDA has been linked to long-term adverse
neurodevelopmental outcome, though it is unclear whether this is caused
by the surgery itself or the anaesthesia [20,21]. Evidence for a causal
relationship between ligation and development of CLD is clearer [22].
The second major argument against intervention is
that PDA is a physiological event in preterm infants and no benefit is
derived from its closure. If left untreated, the natural history of PDA
is ‘likely closure’. Ductus arteriosus (DA) provides a
pulmonary-to-systemic circulatory diversion during fetal life, when
pulmonary blood flow is minimal and pulmonary vascular resistance (PVR)
is high [8,23]. Premature DA closure in fetal life results in a cascade
of events, eventually leading to pulmonary hypertension in the newborn
with possible right ventricular failure in a range of severities.
Immediately after birth, PVR decreases rapidly due to lung expansion and
an increase in partial pressure of oxygen, with an accompanying
five-fold decrease in pulmonary artery pressure and a 7- to 10-fold
increase in pulmonary blood flow [8,23]. In term infants without lung
disease, a functional closure of the DA can be documented using
echocardiography by age of 3 days. Even with the presence of significant
lung disease, DA usually closes within 5 days in preterm infants (>30 wk
gestation) [8].
Trials aimed at closing the PDA provide us with the
information needed to improve our judgment in terms of overall morbidity
and efficacy of therapy. Closure should result in a reduction in the
incidence of PDA-related morbidities. A review by Knight, et al.
[9] examined three groups – prophylactic, pre-symptomatic and
sympto-matic therapy – and showed either a reduction in the incidence of
PDA or symptomatic PDA. However, there were no intergroup differences
regarding death, CLD, ROP or NEC [5,9,15,17,18,24].
To Treat or Not to Treat?
After going through the evidence, physicians are left
with two opposing schools of thought - one advocating treatment and the
other advocating no treatment. However, infants with a birth weight <800
g are at risk of significant morbidity and mortality from PDA and the
natural course in this group is uncertain. In this group, it would be
reasonable to treat PDA when the infant is symptomatic and on mechanical
ventilation. Such high-risk infants can be identified by
echocardiography at 24-30 hours of age, and those having a large PDA can
be treated with cyclooxygenase (COX) inhibitors [25]. Infants with a
small-to-moderate PDA could be managed conservatively and if required,
treatment could be deferred for 7-14 days, to allow spontaneous PDA
closure [25,26]. Infants weighing >800g are unlikely to need treatment
unless they are ventilator-dependent and show evidence of congestive
heart failure or renal failure. In these cases, it is reasonable to
leave the decision to treat at the clinician’s discretion [26].
Our own unpublished audit shows that infants born at
23-25 wk gestation with no antenatal steroid exposure are at the highest
risk of PDA-related morbidities. These infants would benefit from
prophylactic low-dose indomethacin treatment for prevention of
intraventricular hemorrhage (IVH) [27]. However, a targeted neonatal
echocardiographic examination prior to treatment is preferable to
exclude duct-dependent congenital heart disease and significant
right-to-left shunt across the duct.
Management Strategies
Clinicians have five management options for dealing
with PDA in preterm infants: (1) prophylactic pharmacologic treatment
(COX inhibitors), (2) pre-symptomatic pharmacologic treatment of PDA,
(3) conservative management, (4) pharmacological closure of the PDA, and
(5) surgical ligation.
Prophylactic Pharmacotherapy
Prophylactic pharmacotherapy is the practice of
administering COX inhibitors (indomethacin or ibuprofen) to preterm
infants within the first 24h of life irrespective of the diagnosis of
PDA. Dose and interval of indomethacin is 0.1mg/kg at 12h intervals or
0.2 mg/kg at 24h intervals [28]. In the majority of studies, 3 doses
were used starting at 6-12h of age. Ment, et al. [29] and Cower,
et al. [29] used 5 and 6 doses, respectively. With ibuprofen,
most studies used 3 doses starting from 2 to 6 h of age (1st dose was 10
mg/kg, followed by the 2nd and 3rd doses of 5 mg/kg at 24h intervals)
[29].
Meta-analyses and systematic reviews of randomized
controlled trials (RCTs) that examined the prophylactic use of COX
Inhibitors for PDA in preterm infants showed a number of short-term
benefits, including reductions in later symptomatic PDA, rate of severe
IVH and the need for surgical ligation. However, there was no evidence
to suggest that it improved the rate of disability-free survival, and
did not routinely recommend it in the management of PDA in preterm
infants.
Pre-symptomatic Pharmacologic Treatment of PDA
Studies that have looked into the pre-symptomatic
treatment of PDA have not demonstrated any advantage in terms of death,
ROP, NEC or bronchopulmonary dysplasia (BPD) [30]. An overall small
reduction in the number of days on supplemental oxygen, especially in
infants weighing <1000 g at birth has been reported [31]. However, as a
whole, randomized trials have shown no benefit in respiratory outcome
when the ductus were treated at a pre-symptomatic stage or when infants
with a birth weight <1000 g were treated early. There was a significant
(RR 0.38, 95% CI 0.26-0.55) reduction in the subsequent need to treat
PDA. The overall experience gained from the prophylactic indomethacin
group suggest that there is not enough evidence to support
presymptomatic treatment [24]. However, this practice may have a role in
infants born within 23-25 wk of gestation, given the high incidence of
PDA requiring treatment in this group. This possibility requires further
investigation [32].
Conservative Management
This includes fluid restriction to <130 mL/kg/d in
preterm infants of more than 4 days of age, high positive end-expiratory
pressure and low inspiratory time (0.35s) [32]. In a prospective study
involving 30 infants of <30 wk gestational age and a mean (SD) birth
weight of 994 g (600-1484 g), conservative management achieved PDA
closure in all infants. Conservative treatment has the obvious advantage
of being devoid of side effects of medication or surgical ligation.
Therefore, it is reasonable to employ conservative PDA management in
preterm infants as the initial management step. However, infants born at
23 to 25 wk gestation were found to have a lower likelihood of
spontaneous PDA closure and a higher risk of treatment failure with
ibuprofen. In this subgroup of infants with significant PDA, treatment
with a COX inhibitor would be acceptable to most clinicians after 48-72
h of life [32].
Pharmacological Closure
Pharmacological treatment of PDA is the mainstay of
treatment if conservative measures fail. To date, indomethacin,
ibuprofen and mefenamic acid have been used; of which indomethacin and
ibuprofen have been extensively studied.
Indomethacin is of proven efficacy in the management
of PDA [33], though availability of indomethacin is now limited. In a
large collaborative study of 3559 infants, clinically significant PDA
was detected in 421 infants, all of whom were randomized to receive
indomethacin or placebo. Functional closure of PDA was achieved within
48 hours in 79% of the indomethacin group compared to 28% in the control
group. Relapse occurred in 33% of responders; many of these relapses did
not require further treatment [5]. Clinically reproducible side effects
of indomethacin treatment include transient renal impairment,
gastrointestinal (GI) hemorrhage and focal GI perforation. It also
reduces prostaglandin-dependent blood flow to the kidneys, GI tract and
brain. Indomethacin interferes with platelet adhesion and therefore
thrombocytopenia is considered a contraindication for its use. However,
the clinical significance of this undesirable effect is unclear.
Most clinicians use short-course regimens (
4
doses) in terms of PDA treatment failure, CLD, IVH and mortality. A
prolonged course has been shown to increase the incidence of NEC [34].
Doses of indomethacin are lower when used for the prevention of IVH
(0.1mg/kg/dose intravenously at 6-12h of postnatal age and at 24h
intervals for 2 additional doses) [34].
Due to concerns about the adverse effects of
indomethacin, other COX inhibitors have been investigated. Ibuprofen has
received the most attention [30]. Two preparations are available:
ibuprofen lysine and ibuprofen THAM. Use of the THAM preparation has
been associated with increased risk of NEC, and has shown a high
frequency of adverse respiratory, renal and GI events [35]. In view of
the side effects, the original trial was stopped after 135 enrolments
and further use of the THAM preparation has been discouraged. Review of
8 RCTs by Wyllie involving 509 infants found no difference between
ibuprofen and indomethacin for the primary outcome measure of failure to
close the PDA [30]. Ibuprofen has fewer adverse effects on kidney
function, but may be associated with increased risk of pulmonary
complications, including CLD and rarely pulmonary hypertension.
Available data support the use of either drug for the treatment of PDA
[36]. A randomized pilot study by Cherif, et al. [37] with 64
VLBW infants has shown that oral ibuprofen is as good as intravenous
ibuprofen in terms of ductal closure, and is associated with fewer side
effects [36]. However, use of oral indomethacin or ibuprofen is confined
to countries where availability or cost prohibits the use of the
intravenous preparation [37]. Larger studies are needed to confirm the
safety and efficacy of oral use compared to parenteral preparation.
There is recent interest in the use of the
non-selective COX inhibitor (peroxidase sites) paracetamol as an
alternative to established COX inhibitors; four cohort studies involving
29 individual cases have been published. Dosage was 60 mg/kg/d for 2-7
days. Most cases were extremely low birth weight (ELBW) infants with a
background history of either failure with or contraindications to COX
inhibitors. Closure was observed in 20/29 cases with first course, with
eventual closure observed in 27/29 cases. The pharmacokinetics of
paracetamol in ELBW infants is not clearly established and its safety,
especially with a high unauthorized dose, is not documented [38]. The
primary question of whether paracetamol results in PDA closure beyond
the natural history of this phenomenon has not yet been answered.
Therefore, its use should be limited to large RCTs to prove its efficacy
and safety.
Surgical Ligation
Surgical ligation is contemplated only when
pharmacological closure is ineffective or is contrain-dicated in a
preterm infant who is hemodynamically unstable due to PDA. A study in
preterm infants (23-28 wk gestation) reported that compared to drug
treatment alone, primary surgery was associated with increased incidence
of neurodevelop-mental impairment (NDI) (adjusted OR 1.79) and BPD
(adjusted OR 2.19). Secondary surgical closure (indomethacin treatment
followed by ligation) was associated with increased odds for NDI (OR
1.53) and CLD (OR 3.1), but decreased adjusted odds for death [39].
To date, no RCT has compared surgical ligation and
multiple courses of indomethacin for persistent PDA in preterm infants.
A study of 61 VLBW infants has shown that a second and third course of
indomethacin was associated with good results in terms of PDA closure.
However, a third course of indomethacin may be associated with an
increased risk of PVL compared to surgical ligation after a failed
second course of indomethacin for persistent PDA [37].
Novel Treatment Approaches
A novel approach by Sperandio, et al. [40] of
escalating the dose of indomethacin stepwise every 12h to reach a
maximum single dose of 1mg/kg has shown an overall closure rate of
98.5%. Adverse effects were comparable to initial non-responders. Study
results were limited due to the retrospective nature of the study and
lack of long-term follow up.
Endoscopic and catheter closure:
Video-assisted thoracic surgery on PDA is a recognized and effective
alternative to traditional surgery, but it requires further study [41].
Experience with transcatheter management of PDA in VLBW infants is
limited and currently inadequate for implementation in routine practice.
Research Issues
The most compelling question in the management of
significant PDA in preterm infants is the outcome of untreated or
conservatively managed infants with a birth weight <800 g compared to
outcome with pharmacological and/or surgical closure. An RCT to address
this issue will be difficult to design, and will likely face sample size
and ethical issues. However, based on current experience and published
evidence, such a study would be relevant and worth addressing in the
near future. Computer-based decision aids to incorporate parental
preferences into the treatment of PDA also merit further attention [42].
Most of the other issues are related to optimal intervention,
complications and long-term outcome in preterm infants treated for PDA.
These issues can be summarized as follows:
• Echocardiogram-assisted individualized dosing
regimens of a COX-inhibitor for pharmacological closure of PDA
• The impact of multiple courses of indomethacin/COX-inhibitors
for pharmacological closure of PDA on long-term outcome in <1000g
birth weight infants compared to surgical or video-assisted
ligations
• The impact of multiple courses of indomethacin
on long-term neurological outcome in preterm infants with PDA
• The long-term outcome of infants with
significant PDA who are treated with video-assisted ductal ligation.
Conclusion
Infants with a birth weight of <800g are at risk of
significant morbidity and mortality from PDA, and it would be reasonable
to treat the PDA in such infants when they are clinically symptomatic
and require positive pressure ventilatory support. However, infants born
at a gestational age of 23-25 wk without antenatal steroid exposure are
at a higher risk of PDA-related morbidities and would benefit from
prophylactic low-dose indomethacin for prevention of IVH. Preterm
infants with a birth weight >800g are unlikely to need treatment for PDA
unless they are ventilator-dependent and showing evidence of congestive
heart failure or renal impairment.
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