Conservative treatment for patent ductus arteriosus in the preterm.
ABSTRACT A patent ductus arteriosus (PDA) is common among preterms, and prophylactic medical treatment has been advocated as the first-line approach. Conservative treatment may result in similar outcome, but without exposure to the harmful side effects of medication. A retrospective analysis revealed a ductal closure rate of 94% after conservative treatment with adjustment of ventilation (lowering the inspiratory time and increasing positive end expiratory pressure) and fluid restriction.
To study prospectively over one year the rate of PDA closure, and morbidity and mortality following conservative treatment.
Prospective study (1 January 2005 - 31 December 2005) including 30 newborns <or=30 weeks' gestation, all of whom were being ventilated and required surfactant. Echocardiography was performed 48-72 h after birth. Clinically important PDA was conservatively treated as described above. The percentage of children with PDA, ductal ligation and major complications was determined.
Ten neonates (33%) developed a clinical important PDA. Following conservative treatment the duct closed in all neonates (100%), and none required ductal ligation or medical treatment. The rates of major complications were no higher than those reported by the Vermont Oxford Network and in the literature.
The managed care plan resulted in an overall ductal closure rate of 100%. These results suggest that conservative treatment of PDA is a worthy alternative to prophylactic medical treatment.
- SourceAvailable from: Dany Weisz[Show abstract] [Hide abstract]
ABSTRACT: Observational studies have associated patent ductus arteriosus (PDA) ligation in preterm infants with increased chronic lung disease (CLD), retinopathy of prematurity, and neurodevelopmental impairment at long-term follow-up. Although the biological rationale for this association is incompletely understood, there is an emerging secular trend toward a permissive approach to the PDA. However, insufficient adjustment for postnatal, pre-ligation confounders, such as intraventricular hemorrhage and the duration and intensity of mechanical ventilation, suggests the presence of residual bias due to confounding by indication, and obliges caution in interpreting the ligation-morbidity relationship. A period of conservative management after failure of medical PDA closure may be considered to reduce the number of infants treated with surgery. Increased mortality and CLD in infants with persistent symptomatic PDA suggests that surgical ligation remains an important treatment modality for preterm infants.Journal of clinical neonatology. 04/2014; 3(2):67-75.
- [Show abstract] [Hide abstract]
ABSTRACT: The purpose of this study was to evaluate prognostic factors associated with surgical ligation for patent ductus arteriosus (PDA) in extremely preterm infants born at the limits of viability. Ninety infants who were born at 23-25 weeks of gestation and who received surgical ligation were included and their cases were retrospectively reviewed. Infants were classified into two different groups: survivors with no major morbidity (N), and non-survivors or survivors with any major morbidity (M). Clinical characteristics were compared between the groups. Possible prognostic factors were derived from this comparison and further tested by logistic regression analysis. The mean gestational age and the mean birth weight of M were significantly lower than those of N. Notably, the mean postnatal age at time of ligation in N was significantly later than that of the other group (17±12 vs 11±8 days in N and M, respectively). An adjusted analysis showed that delayed ligation (>2 weeks) was uniquely associated with a significantly decreased risk for mortality or composite morbidity after surgical ligation (OR, 0.105; 95% CI, 0.012-0.928). In conclusion, delayed surgical ligation for PDA (>2 weeks) is associated with decreased mortality or morbidities in extremely preterm infants born at 23-25 weeks of gestation.Journal of Korean medical science 04/2014; 29(4):581-6. · 0.84 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Background and Aims:Previous studies have mainly looked at the significance of biochemical markers in predicting significant patent ductus arteriosus (PDA) within the first week of life. The aim of the study was to assess the value of plasma N-terminal pro-brain natriuretic peptide (NT-proBNP) concentration as a predictor of PDA in very preterm infants beyond the first week of life.Pediatric Research 11/2011; · 2.84 Impact Factor
Conservative treatment for patent ductus arteriosus in the
Sophie Vanhaesebrouck, Inge Zonnenberg, Piet Vandervoort, Els Bruneel, Marie-Rose Van
Hoestenberghe, Claire Theyskens
............................................................... ............................................................... .....
See end of article for
Dr Claire Theyskens,
Ziekenhuis Oost Limburg,
Campus Sint-Jan, Schiepse
Bos 6, B-3600 Genk,
Accepted 3 January 2007
Published Online First
9 January 2007
Arch Dis Child Fetal Neonatal Ed 2007;92:F244–F247. doi: 10.1136/adc.2006.104596
Background: A patent ductus arteriosus (PDA) is common among preterms, and prophylactic medical
treatment has been advocated as the first-line approach. Conservative treatment may result in similar
outcome, but without exposure to the harmful side effects of medication. A retrospective analysis revealed a
ductal closure rate of 94% after conservative treatment with adjustment of ventilation (lowering the inspiratory
time and increasing positive end expiratory pressure) and fluid restriction.
Objective: To study prospectively over one year the rate of PDA closure, and morbidity and mortality
following conservative treatment.
Method: Prospective study (1 January 2005 – 31 December 2005) including 30 newborns (30 weeks’
gestation, all of whom were being ventilated and required surfactant. Echocardiography was performed 48–
72 h after birth. Clinically important PDA was conservatively treated as described above. The percentage of
children with PDA, ductal ligation and major complications was determined.
Results: Ten neonates (33%) developed a clinical important PDA. Following conservative treatment the duct
closed in all neonates (100%), and none required ductal ligation or medical treatment. The rates of major
complications were no higher than those reported by the Vermont Oxford Network and in the literature.
Conclusion: The managed care plan resulted in an overall ductal closure rate of 100%. These results suggest
that conservative treatment of PDA is a worthy alternative to prophylactic medical treatment.
ductus arteriosus (PDA) in preterm neonates varies from 40%
to 60% on the third day of life, depending on estimated
gestational age. Therefore, it continues to be one of the
commonest problems in preterm neonates.1–9
It is important to make distinguish between a clinically
significant and non-significant PDA.1 2 5 10A clinically impor-
tant PDA is characterised by respiratory problems with
ventilation difficulties, metabolic acidosis, and pulmonary
congestion with tachycardia and bounding pulses. The con-
sequence of this left-to-right shunt is an increased risk of
complications, including intraventricular haemorrhage (IVH),
necrotising enterocolitis (NEC), chronic lung disease (CLD) and
death. Hence, PDA affects key outcome variables of early
preterm life.3 5 11–15
Currently, many preterm care units implement systematic
treatment of PDA with ibuprofen or indometacin. On the basis
of studies comparing the efficacy and safety of both drugs,
ibuprofen has been proposed as the drug of choice: the rate of
closure of PDA was comparable with both drugs, but ibuprofen
was associated with fewer side effects.1 4 12 16However, con-
troversy still exists about the optimal timing for starting
ibuprofen (prophylactic or therapeutic).17An important issue
is the lack of documentation of side effects, especially long term
side effects following its prophylactic use.6 17Moreover, its value
is still questionable, as data remain scanty on the outcome of
PDA following conservative treatment according to current
Current conservative treatments include
adjustment of ventilation by reducing inspiratory time and
giving more positive end expiratory pressure (PEEP), and fluid
restriction not exceeding 130 ml/kg a day beyond day 3.2With
the use of this procedure, we have noticed a high closure rate of
PDA at our centre. Therefore, with the aim of establishing the
he ductus arteriosus closes spontaneously in most full-term
infants during the first three days of life, but in preterm
neonates it often fails to close. The incidence of patent
best possible managed care plan, we prospectively quantified
the outcome of PDA closure and its complications in our
preterm population, and evaluated whether prophylactic
ibuprofen is needed.
We retrospectively analysed all medical records in the neonatal
intensive care unit at the hospital of Genk, Belgium, from 1
January 1999 to 31 December 2004 (fig 1; table 1). PDA was
initially clinically diagnosed based on the detection of murmur,
deterioration of respiratory function, metabolic acidosis and/or
blood pressure problems. Treatment was started on a clinical
basis, and the diagnosis was confirmed by echocardiography
(DA diameter >1.4 mm, completed with Doppler colour flow).
After conservative treatment, the remaining patency of PDA
was confirmed echocardiographically. If the duct had failed to
close, it was ligated.
On the basis of the excellent results of the retrospective
analysis a managed care plan was developed. We then
undertook a prospective study in our neonatal unit from 1
January 2005 to 31 December 2005. Neonates were eligible if
born at (30 weeks’ gestation, if they were being ventilated and
required surfactant replacement. Echocardiography was carried
out for every neonate 48–72 h after birth. All infants with PDA
were treated following our centre’s standard protocol as soon as
a diagnosis of an haemodynamically important PDA was made
(DA diameter >1.4 mm, completed with Doppler colour flow):
conservative treatment consisting of fluid restriction (max-
imum 130 ml/kg a day beyond day 3) and adjustment of
ventilation by lowering inspiratory time to as low as 0.35 s, and
Abbreviations: CLD, chronic lung disease; IVH, intraventricular
haemorrhage; NEC, necrotising enterocolitis; PDA, patent ductus
arteriosus; PEEP, positive end expiratory pressure
giving higher PEEP (as high as 4.5 mbar). (Usual practice in
our ward includes inspiratory time 0.4–0.45 s and PEEP 3.5–
4.0 mbar.) For a PDA that did not show clinical improvement
and/or deteriorated, and for continuing need for ventilatory
support, ductal ligation was carried out. All other PDAs closed
with conservative treatment. We did not use any medication for
prophylactic or therapeutic treatment of PDA.
Outcome was assessed by analysing the percentage of
children with PDA, ductal ligation and major complications.
The rate of occurrence of NEC (Bell staging 2–3), IVH grade 3,
CLD n-continuous positive airways pressure (nCPAP) and/or
oxygen need beyond 36 weeks’ gestational age) and death were
compared with data from the Vermont Oxford Network and the
data on outcome with ibuprofen and/or indometacin, as
Patent ductus arteriosus
A total of 30 neonates (46% boys, 54% girls; mean gestational
age 26.6 weeks (range 25–30 weeks); mean birth weight 994 g
(600–1484 g)) were included in the analysis (fig 2). The infants
with and without PDA did not differ significantly with regard
to birth weight and gestational age (Mann Whitney U test,
fig 3). The median gestational age of two groups was 27
(interquartile range 26–28) weeks and 28 (interquartile range
26–30) weeks, respectively. The median birth weight of the
group with PDA was 1010 g (interquartile range 825–1425 g)
and of the group without PDA was 926 g (interquartile range
785–1208 g). Figure 2 illustrates the outcome of the study
population: 20 neonates (67%) had no clinical significant PDA
and therefore received no extra treatment. Clinically important
PDA was found in 10 neonates (33%). Adjustment of
ventilation and fluid restriction led to closure of all PDAs.
Ductal ligation was not needed.
Overall, none of the infants in this series developed NEC; 2%
developed IVH and 7% developed CLD (Table 2). According to
the records, total mortality (any cause) added up to 12% during
stay in the unit.
PDA continues to be a common problem among preterm
infants. Although many studies have been published on
medical and surgical treatment, only few studies have
evaluated the outcome of current conservative treatment that
includes adjusting ventilation and fluid restriction. Moreover,
ibuprofen appears to have been mainly evaluated against
indometacin, and prophylactic studies seem to have defined
success by the status of ductal closure on day 3 of life, rather
than considering the overall outcome.17
conservatively managed preterm neonates (30 weeks’ gestation,
requiring ventilation and surfactant treatment (retrospective analysis). PEEP,
positive end expiratory pressure; Ti, inspiratory time.
Occurrence of patent ductus arteriosus (PDA) in 109
preterm neonates (30 weeks’ gestation, requiring
ventilation and surfactant treatment: comparison with data
from the Vermont Oxford Network
Complications in 109 conservatively managed
Proportion (%) of neonates with
Chronic lung disease
*See Methods: Adjusment of ventilation and fluid restriction, and if PDA still
present, ductal ligation carried out
?Range based on data from the Vermont Oxford Network and data on
outcome with ibuprofen and/or indometacin, as provided by Orphan
arteriosus (PDA) in 30 conservatively managed preterm neonates (30
weeks’ gestation, requiring ventilation and surfactant treatment. PEEP,
positive end expiratory pressure; Ti, inspiratory time.
Flow chart of prospective study of occurrence of patent ductus
Conservative treatment of PDA F245
In our population of preterm babies of (30 weeks’ gesta-
tional age, 72% had spontaneous closure of PDA. The children
who had a clinically important PDA (28%) (echocardiographi-
cally confirmed) were all conservatively treated as soon as
diagnosis was made. With fluid restriction to a maximum of
130 ml/kg/day beyond day 3 and adjustment of ventilation by
decreasing inspiratory time and increasing PEEP, the PDA
closed in another 22%, resulting in a total closure rate of 94%.
This rate compares well with the rates reported in literature
following medical treatment (80–92%).1 2 6 13 15 16 18
Given that our retrospective analysis revealed a PDA closure
rate of 94% after conservative treatment, we wondered whether
prophylactic ibuprofen, the currently recommended drug of
choice, was indicated. We postulated that a high rate of PDA
closure could be achieved with conservative treatment, thereby
avoiding potential side effects of medical treatment. Our
excellent retrospective results were confirmed in the prospec-
tive study with even more convincing results (an overall closure
rate of 100%).
Ibuprofen is widely used for prophylaxis. Compared with
indometacin, it is associated with a lower risk of oliguria.12
Prophylactic use of ibuprofen has no major influence on
reducing morbidity or the need of surgical PDA closure.11
Importantly, one study showed an increased risk of pulmonary
hypertension and had to be terminated early.6An increased
incidence of NEC was also reported in the treatment group in
that study.6Hammerman and Kaplan recently observed that
‘‘ibuprofen is not as benign as implied by much of the PDA
literature’’: early postnatal administration in small premature
neonates may be associated with more complications than later
therapeutic use, after further postnatal maturation.17The 2003
Cochrane systematic review on ibuprofen prophylaxis con-
cluded that although prophylactic ibuprofen use reduces the
incidence of PDA on day 3, the potential adverse effects should
be further addressed, along with neurodevelopmental out-
Our results indicate that ibuprofen prophylaxis would have
unnecessarily exposed the majority of our preterm neonates to
the risk of side effects. At least for the acute treatment of PDA,
a Cochrane review in 2003 concluded that the data on net
benefit/harm were insufficient to conclude whether surgical
ligation or medical treatment is preferred as initial treatment
for symptomatic PDA in preterm infants.3As the rate of
complications in our study population compared well with the
currently established reference rates using medication (table 1
and 2), our findings further support our approach (figs 1 and 2)
as a favourable alternative to medication prophylaxis and a
valid managed care plan.
In conclusion, the rate of PDA closure achieved with
conservative treatment at our centre was comparable to the
rates previously reported with drug prophylaxis. Although our
approach resulted in a similar risk profile for major complica-
tions, it did so without exposing the neonates to potential side
effects of drug treatment. The results of our retrospective
analysis were confirmed prospectively with even better results.
Therefore, we postulate that prophylactic use of ibuprofen is
not indicated and that conservative treatment by means of
adjusting ventilation (inspiratory time as low as 0.35 s and
PEEP as high 4.5 mbar) and fluid restriction (130 ml/kg/day
beyond day 3) is a more favourable alternative, following the
first law of medicine ‘‘primum non nocere’’.
(PDA) according to gestational age.
Distribution of infants with and without a patent ductus arteriosus
managed preterm neonates (30 weeks’ gestation,
requiring ventilation and surfactant treatment: comparison
with data from the Vermont Oxford Network
Occurrence of complications in 30 conservatively
Proportion (%) of neonates developing
Chronic lung disease
*See Methods: Adjustment of ventilation and fluid restriction, and if PDA still
present, ductal ligation.
?Range based on the data from the Vermont Oxford Network and data on
outcome with ibuprofen and/or indometacin, as provided by Orphan
What is already known on this topic
N Many preterm care units implement systematic treatment
of patent ductus arteriosus (PDA) with ibuprofen or
indometacin. Ibuprofen has been proposed as the drug
of choice as closure rates of PDA are comparable with
both but ibuprofen is associated with fewer side effects.
N Controversy still exits about the optimal timing for starting
this treatment (prophylactic or therapeutic).
N There is a lack of documentation of side effects following
prophylactic use of ibuprofen, especially in the long term.
N Its value remains questionable, as data are scanty on the
outcome of PDA following conservative treatment
according to current standards.
What this study adds
N The results of this study do not support the use of
pharmacological treatment with ibuprofen, as proposed
by some centres.
N Conservative treatment avoids exposure of preterm
infants to potential side effects of medication.
N This findings of this study are therefore relevant to the
international medical community.
F246 Vanhaesebrouck, Zonnenberg, Vandervoort, et al
To confirm our results, we recommend carrying out
prospective multicentre randomised controlled trials with larger
patient samples comparing conservative treatment (with
placebo) with pharmacological treatment.
We thank Suzy Huijghebaert for assisting us in preparing and
submitting this manuscript.
Sophie Vanhaesebrouck, Inge Zonnenberg, Els Bruneel, Marie-Rose Van
Hoestenberghe, Claire Theyskens, Neonatal Intensive Care, Ziekenhuis
Oost Limburg, Genk, Belgium
Piet Vandervoort, Cardiology, Ziekenhuis Oost Limburg, Genk, Belgium
Competing interests: None.
Ethics committee approval and patient consent: Not needed (analysis of
outcome of standard procedure in our unit).
1 Van Overmeire B, Follens I, Hartman S, et al. Treatment of patent ductus
arteriosus with ibuprofen. Arch Dis Child Fetal Neonatal Ed 1997;76:F179–84.
2 Wyllie J. Treatment of patent ductus arteriosus. Semin Neonatol 2003;8:
3 Malviya M, Ohlsson A, Shah S. Surgical versus medical treatment with
cyclooxygenase inhibitors for symptomatic patent ductus arteriosus in preterm
infants. Cochrane Database Syst Rev 2003;3:CD003951.
4 Flores M. Ibuprofen: alternative treatment for patent ductus arteriosus. Neonatal
5 Knight DB. The treatment of patent ductus arteriosus in preterm infants. A review
and overview of randomized trials. Semin Neonatol 2001;6:63–73.
6 Gournay V, Roze JC, Kuster A, et al. Prophylactic ibuprofen versus placebo in
very premature infants: a randomised, double-blind, placebo-controlled trial.
7 Furzan JA, Reisch J, Tyson JE, et al. Incidence and risk factors for symptomatic
patent ductus arteriosus among inborn very-low-birth-weight infants. Early Hum
8 Mouzinho AI, Rosenfeld CR, Risser R. Symptomatic patent ductus arteriosus in
very-low-birth-weight infants: 1987–1989. Early Hum Dev 1991;27:65–77.
9 Koch J, Hensley GH, Roy L, et al. Prevalence of spontaneous closure of the ductus
arteriosus in neonates at a birth weight of 1000 grams or less. Pediatrics
10 Hammerman C, Strates E, Valaitis S. The silent ductus: its precursors and its
afterdeath. Pediatr Cardiol 1986;7:121–7.
11 Shah SS, Ohlsson A. Ibuprofen for the prevention of patent ductus arteriosus in
preterm and/or low birth weight infants. Cochrane Database Syst Rev
12 Ohlsson A, Walia R, Shah S. Ibuprofen for the treatment of a patent ductus
arteriosus in preterm and/or low birth weight infants. Cochrane Database Syst
13 Koehne PS, Bein G, Alexi-Meskhishvilli V, et al. Patent ductus arteriosus in very
low birthweight infants: complications of pharmacological and surgical
treatment. J Perinat Med 2001;29:327–34.
14 Brooks JM, Travadi JN, Patole SK, et al. Is surgical ligation of patent ductus
arteriosus necessary? The Western Australian experience of conservative
management. Arch Dis Child Fetal Neonatal Ed 2005;90:F190.
15 Fowlie PW, Davis PG. Prophylactic intravenous indomethacin for preventing
mortality and morbidity in preterm infants. Cochrane Database Syst Rev
16 Van Overmeire B, Allegaert K, Casaer A, et al. Prophylactic ibuprofen in
premature infants: a multicentre, randomised, double-blind, placebo-controlled
trial. Lancet 2004;364:1945–9.
17 Hammerman C, Kaplan M. Primum non nocere: prophylactic versus curative
ibuprofen. Lancet 2004;364:1920–2.
18 Cooke L, Steer P, Woodgate P. Indomethacin for asymptomatic patent ductus
arteriosus in preterm infants. Cochrane Database Syst Rev 2003;2:CD003745.
19 Vermont Oxford Network. http://www.vrtoxford.org.
20 Varvarigou A, Bardin CL, Beharry K, et al. Early ibuprofen administration to
prevent patent ductus arteriosus in premature newborn infants. JAMA
21 Mosca F, Bray M, Lattanzio M, et al. Comparative evaluation of the effects of
indomethacin and ibuprofen on cerebral perfusion and oxygenation in preterm
infants with patent ductus arteriosus. J Pediatr 1997;131:549–54.
22 Pezzati M, Vangi V, Biagiotti R, et al. Effects of indomethacin and ibuprofen on
mesenteric and renal blood flow in preterm infants with patent ductus arteriosus.
J Pediatr 1999;135:733–8.
23 Dani C, Bertini G, Reali M F, et al. Prophylaxis of patent ductus arteriosus with
ibuprofen in preterm infants. Acta Paediatr 2000;89:1369–74.
24 De Carolis MP, Romagnoli C, Polimeni V, et al. Prophylactic ibuprofen therapy of
patent ductus arteriosus in preterm infants. Eur J Pediatr 2000;159:364–8.
25 Patel J, Roberts I, Azzopardi D, et al. Randomized double-blind controlled trial
comparing the effects of ibuprofen with indomethacin on cerebral hemodynamics
in preterm infants with patent ductus arteriosus. Pediatr Res 2000;47:36–42.
26 Van Overmeire B, Smets K, Lecoutere D, et al. A comparison of ibuprofen and
indomethacin for closure of patent ductus arteriosus. N Engl J Med
Save your favourite articles and useful searches
Use the ‘‘My folders’’ feature to save and organise articles you want to return to quickly—saving
space on your hard drive. You can also save searches, which will save you time. You will only
need to register once for this service, which can be used for this journal or all BMJ Journals,
including the BMJ.
Conservative treatment of PDAF247