Management of Persistent Ductus Arteriosus (PDA)

Background
PDA is a common complication of prematurity, affecting 60% of babies under 28
weeks gestation. It is associated (not necessarily causally) with neonatal morbidities
including IVH, NEC and CLD. Antenatal steroids and restricted fluid intake in the
early neonatal period are associated with a reduced risk of PDA. It is generally
accepted that symptomatic PDA warrants medical and/or surgical intervention,
although the criteria for diagnosis of a significant PDA remain controversial.
Management strategies
There are three main ways of managing PDA in preterm infants: prophylactic
therapy, early asymptomatic treatment and treatment of the symptomatic PDA. The
two drugs most widely used for pharmacological closure of the ductus are
indometacin and ibuprofen, both of which work by interfering with prostaglandin
synthesis through cyclo-oxygenase inhibition.

a) Prophylaxis
Prophylactic therapy offers the benefit of closing the ductus at the earliest
opportunity, but carries the risk of exposing babies who were never destined to
develop a symptomatic PDA to a potentially harmful drug.
Prophylactic indomethacin is effective in reducing the incidence of
symptomatic PDA (NNT = 4) and the need for surgical ligation of PDA (NNT=20).[1]
It is also effective in reducing the risk of severe IVH (NNT = 20) and PVL/white
matter injury (NNT = 20). However, there is no evidence of benefit in terms of
medium to long-term outcomes such as CLD and neurodevelopmental status.
Although there are some theoretical concerns about the effects of indometacin on
cerebral, gut and renal blood flow, there is no convincing evidence that prophylactic
indomethacin is associated with an increase in adverse clinical outcomes such as
NEC, persistent renal dysfunction or ischaemic brain injury.
Prophylactic ibuprofen is also effective in reducing the risk of symptomatic
PDA and surgical ligation, but does not confer any benefit in terms of IVH or white
matter injury.[2] There is no information about long term outcome following ibuprofen
prophylaxis.
b) Early asymptomatic treatment
Treating the ductus at an early pre-symptomatic stage on the basis of pre-defined
echocardiographic criteria may be theoretically preferable to prophylactic therapy
because it allows targeted treatment of babies before they develop a symptomatic
PDA. However, a meta-analysis of three small randomised controlled trials of
indometacin for early asymptomatic treatment of PDA failed to demonstrate any
important clinical benefits with this strategy.[3] This approach cannot be
recommended at present although there are ongoing trials evaluating the
effectiveness of this strategy.
c) Treatment of a symptomatic PDA
The commonest approach to management of the ductus is to defer treatment until a
baby becomes symptomatic and has echocardiographic criteria confirming a
significant ductal shunt. Although this strategy allows treatment to be restricted to
those babies who actually have a significant PDA, it will inevitably result in babies

receiving treatment only after they have developed signs of cardiorespiratory
compromise. One trial comparing early (d3) versus later (d7) indomethacin therapy
for moderately large PDA did not demonstrate any important clinical benefits of early
symptomatic treatment.[4]

Diagnosis of PDA
Diagnosis of symptomatic PDA based solely on clinical criteria is unreliable.[5]
2D/Doppler echocardiography is the gold standard for (1) diagnosing PDA and
quantifying the likely magnitude of any ductal shunt and (2) exclusion of other
cardiac defects including duct-dependent lesions prior to attempted ductal closure.

Treatment of symptomatic PDA

1. Fluid restriction/diuretics
Although fluid restriction and diuretic therapy is widely advised and practised, there
is little evidence supporting the routine use of either treatment in the management of
symptomatic PDA. Fluid restriction is associated with compromised nutritional intake
and poor growth. Diuretics such as furosemide often result in electrolyte
derangements and are themselves associated with prolonged ductal patency.
Nevertheless, there may be a role for using diuretics to control symptoms in
some babies with PDA and evidence of left heart failure whilst awaiting spontaneous
closure, or in those in whom other pharmacological or surgical treatment is
contraindicated or delayed (eg. those with pulmonary haemorrhage).[6]


2. Pharmacological closure

Note: Indometacin is currently not available because of unspecified manufacturing
problems.

Indometacin and ibuprofen are both licensed preparations for treatment of
symptomatic PDA in preterm babies. Randomised controlled trials have
demonstrated similar efficacy for ductal closure with ibuprofen compared to
indometacin (approximately 70%). [7] Although ibuprofen is associated with
less disruption of cerebral blood flow, less renal impairment and tendency to
less NEC, it may equally be associated with a prolonged oxygen
requirement.[8] There is no information on long-term neurodevelopmental
outcome after ibuprofen or indometacin therapy for symptomatic PDA.

Anecdotally, repeat treatment with indometacin or ibuprofen is sometimes
used but is rarely successful.

There is no evidence to support the practice of withholding enteral feeds in
babies receiving drug treatment for ductal closure.



3. Ductal ligation
Although ductal ligation is more effective than indomethacin for achieving permanent
ductal closure when used as first line therapy in symptomatic PDA, there is no
evidence of a benefit in terms of important neonatal outcomes.[9] Ligation is also
associated with significant morbidity (1-16%, including pneumothorax, chylothorax,
haemorrhage and wound infection) and mortality (0-10%).[10] There is also some
evidence that ductal ligation is itself independently associated with important short
and long term adverse clinical outcomes, including CLD, ROP and neurodisability at
18 months.[11]


Action
1. Preterm babies, especially those < 28 weeks and/or < 1000g, should be examined
regularly for signs of a symptomatic PDA.

2. Babies with a suspected symptomatic PDA on clinical grounds should have an
echocardiogram performed to confirm or refute the diagnosis prior to treatment.

3. Only babies with a symptomatic (haemodynamically significant) PDA, confirmed
echocardiographically, should be considered for pharmacological ductal closure.
The decision to treat a symptomatic PDA should be made following discussion
with a Consultant.

4. Restriction of fluid intake and/or diuretics should not be used routinely in the
management of symptomatic PDA, but may be useful as symptomatic therapy in
some babies with evidence of left heart failure.

5. Ibuprofen should be used as the first line agent for the treatment of symptomatic
PDA. Refer to the Drug Information Folder for the dosage regimen.

6. A second treatment course of ibuprofen for symptomatic PDA should not be used
routinely but may be appropriate in selected cases.

7. Surgical closure is indicated in babies with a symptomatic PDA who have
contraindications to pharmacological treatment or in whom medical treatment has
failed.





References

1. Fowlie PW, Davis PG, McGuire W. Prophylactic intravenous indomethacin for
preventing mortality and morbidity in preterm infants.Cochrane Database Syst Rev.
2010 Jul 7;(7):CD000174.
2. Shah SS, Ohlsson A. Ibuprofen for the prevention of patent ductus arteriosus in
preterm and/or low birth weight infants.Cochrane Database Syst Rev. 2006 Jan
25;(1):CD004213.

3. Cooke L, Steer P, Woodgate P. Indomethacin for asymptomatic patent ductus
arteriosus in preterm infants.Cochrane Database Syst Rev. 2003;(2):CD003745.
4. Van Overmeire B, Van de Broek H, Van Laer P, Weyler J, Vanhaesebrouck P.
Early versus late indomethacin treatment for patent ductus arteriosus in premature
infants with respiratory distress syndrome.J Pediatr. 2001 Feb;138(2):205-11.
5. Skelton R, Evans N, Smythe J.A blinded comparison of clinical and
echocardiographic evaluation of the preterm infant for patent ductus
arteriosus. J Paediatr Child Health. 1994 Oct;30(5):406-11.

6. Wyllie J. Treatment of patent ductus arteriosus. Semin Neonatol. 2003
Dec;8(6):425-32.

7. Ohlsson A, Walia R, Shah SS. Ibuprofen for the treatment of patent ductus
arteriosus in preterm and/or low birth weight infants. Cochrane Database Syst Rev.
2010 Apr 14;(4):CD003481.

8. Van Overmeire B, Smets K, Lecoutere D, Van de Broek H, Weyler J,Degroote K,
Langhendries JP. A comparison of ibuprofen and indomethacin for closure of patent
ductus arteriosus. N Engl J Med. 2000 Sep 7;343(10):674-81.

9. 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.

10. Van Overmeire B, Chemtob S. The pharmacologic closure of the patent
ductus arteriosus. Semin Fetal Neonatal Med. 2005 Apr;10(2):177-84.
Epub 2004 Dec 15.
11. Kabra NS, Schmidt B, Roberts RS, Doyle LW, Papile L, Fanaroff A; Trial of
Indomethacin Prophylaxis in Preterms Investigators. Neurosensory impairment after
surgical closure of patent ductus arteriosus in extremely low birth weight infants:

results from the Trial of Indomethacin Prophylaxis in Preterms. J Pediatr. 2007
Mar;150(3):229-34, 234.e1.


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