1. pharmacology reviews
Pharmacologic Closure of
Patent Ductus Arteriosus in
the Neonate
Meera Narayanan-Sankar MD*, Ronald I. Clyman MD†
Objectives After completing this article, readers should be able to:
1. Delineate the factors regulating patent ductus arteriosus (PDA) and the two
stages of closure of PDA.
2. Detail the medical treatment of PDA with indomethacin.
3. Explain the role of ibuprofen in treating PDA.
4. Discuss other agents and novel therapeutic approaches for PDA.
Introduction left-to-right shunt in preterm infants.
PDA is a common complication This has resulted in a greater per-
that occurs in more than 70% of ceived need by physicians to treat
very low-birthweight infants who PDA.
have respiratory distress syndrome The clinical consequences of
(RDS). Burnard initially noted in PDA are related to the degree of
1939 that murmurs were more left-to-right shunting through the
common among infants who had ductus. The blood flow distribution
respiratory distress, and he sug- is altered by the decrease in dia-
gested the possibility of PDA in stolic pressure and localized vaso-
affected infants. The presence of a constriction. The reduced organ
ductal left-to-right shunt shortly af- perfusion contributes to some of
ter birth in normal term infants was the morbidity caused by PDA, in-
inferred from dye dilution studies cluding feeding intolerance, necro-
by Prec and Cassels and from car- tizing enterocolitis, and decreased
diac catheterization studies by glomerular filtration rate. PDA also
Adams and Lind and by Rowe and exposes the pulmonary microvascu-
James. The first reported catheter- lature to systemic blood pressure
ization proof of PDA in preterm and increased pulmonary blood
infants who had RDS was provided
flow. Because the preterm infant
by Rudolph and coworkers in
who has RDS frequently has low
1961.
plasma oncotic pressure and in-
Exogenous surfactant therapy has
creased capillary permeability, an
altered both the incidence and pre-
increase in pulmonary microvascu-
sentation of PDA. Although surfac-
lar pressures increases interstitial
tant has no effect on the contractile
and alveolar lung fluid. The in-
behavior of the ductus, its effects on
crease in oxygen concentration and
pulmonary vascular resistance lead to
mean airway pressures needed to
an earlier clinical presentation of the
overcome these changes in lung
compliance may be important fac-
*Fellow in Pediatrics, Division of Neonatal-Perinatal tors in the development of chronic
Medicine, University of California, Davis, Davis, CA. lung disease.
†
Professor of Pediatrics, Division of Neonatal-
Perinatal Medicine, University of California, San The incidence of PDA is inversely
Francisco, San Francisco, CA. related to the maturity of the infant.
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2. pharmacology reviews
In term newborns, the ductus closes growth factor-beta, which play early lumen and those of the vasa vasorum
within 24 to 48 hours after delivery. roles in ductal remodeling. invading its outer muscle media. The
However, in preterm newborns, the In contrast to term infants, the relative importance of the two vaso-
ductus frequently fails to close. As a ductus in preterm infants frequently dilators, PGE2 and NO, in maintain-
result, 70% of preterm newborns de- remains open for several days after ing ductal patency changes after
livered before 28 weeks’ gestation birth. Even when it does constrict, birth. With advancing postnatal age,
require either medical or surgical clo- profound hypoxia and anatomic re- dilator PGs no longer may be the
sure of PDA. In this review, we sum- modeling often fail to develop, which dominant factor in maintaining pa-
marize factors that regulate patency leads to subsequent ductal reopen- tency. These findings are consistent
of the ductus arteriosus, describe the ing. Preterm infants require more with recent clinical observations that
standard pharmacologic treatment of ductal constriction to produce the the PG inhibitor indomethacin is
PDA with indomethacin, and com- same level of ductal wall hypoxia as is much more likely to close the ductus
pare standard treatment with the re- found at term. If the same level of if administered on the first day after
cent use of ibuprofen. Finally, we hypoxia can be induced in the pre- birth. In preterm baboons, the com-
describe novel approaches to PDA term ductus, most of the anatomic bined use of an NO inhibitor and
treatment that are in the investiga- changes that occur in term infants indomethacin produced a much
tional stage. will occur in preterm infants. greater degree of ductus constriction
Closure of the ductus arteriosus at than indomethacin alone. Drugs that
Factors Regulating Patency birth depends on an alteration in the interfere with NO synthesis could
of the Ductus Arteriosus balance between dilating and con-
become a useful adjunct, especially in
In the term infant, closure of the stricting factors. Since the initial
situations where indomethacin has
ductus arteriosus occurs in two studies of Kennedy and Clark, many
proved to be ineffective.
phases. Initial smooth muscle con- investigators have demonstrated that
striction produces a “functional” clo- oxygen plays an important role in
sure of the lumen within hours after ductus arteriosus constriction after
Indomethacin: An Alternative
birth. This is followed by “anatomic” birth. However, the biochemical ba-
to Surgical Ligation
occlusion of the lumen over the next sis of the oxygen response never has
Surgical ligation of a symptomatic
several days caused by extensive neo- been explained fully.
PDA in preterm infants can be per-
intimal thickening and loss of We have a much better under-
formed in the neonatal intensive care
smooth muscle cells from the inner standing of the factors that oppose
unit with low mortality and morbid-
muscle media. This initial functional ductus constriction. The ductus pro-
ity. However, respiratory compro-
constriction of the ductus produces a duces several vasodilator substances
zone of ischemic hypoxia in the mus- that inhibit the ability of oxygen to mise, blood pressure fluctuations, in-
cle media of the ductus that appears constrict the ductus. Vasodilator tracranial hemorrhage, infection,
to be the necessary signal for irrevers- prostaglandins (PGs), PGE2 and chylothorax, recurrent laryngeal
ible anatomic closure. This hypoxic PGI2, play significant roles in main- nerve paralysis, and death remain
zone is associated with local produc- taining ductal patency during fetal risks associated with surgical closure,
tion of hypoxia-inducible growth and neonatal life. PGE2 appears to be especially among infants born at less
factors, such as vascular endothelial the most important prostanoid regu- than 28 weeks of gestation. Inhibi-
growth factor and transforming lating ductal patency. Inhibition of tion of PG synthesis with nonselec-
PG synthesis by inhibition of the en- tive inhibitors of COX appears to be
zyme cyclooxygenase (COX) pro- an effective alternative to surgery for
duces constriction of the ductus in closure of PDA. Over the years, ther-
Abbreviations both animals and humans. In addi- apy with indomethacin, a nonselec-
CBF: cerebral blood flow tion to PGs, the ductus arteriosus tive COX inhibitor, has been ac-
COX: cyclooxygenase produces a nitric oxide (NO)-like va- cepted as effective in mediating
NO: nitric oxide sodilator after birth. Only one of the ductal closure in preterm neonates.
PDA: patent ductus arteriosus three isoforms of nitric oxide syn- However, there is little consensus re-
PG: prostaglandin thase (ecNOS) appears to be located garding proper dosage, treatment
RDS: respiratory distress syndrome in the ductus wall. This is restricted duration, and optimal timing of
to endothelial cells lining the ductus treatment with indomethacin.
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Dose sure rate and to decrease the relapse III/IV intracranial hemorrhage and
Many variations in dosage regimens rate when compared with a shorter pulmonary hemorrhage, its use may
are reported. In most instances, a course (2 to 3 doses over 24 h). be appropriate in infants who are at
single dose has not resulted in persis- However, this dosage regimen needs high risk for developing these com-
tent contraction of the ductus arteri- further evaluation. In some reports, a plications.
osus. The response of the ductus to higher mortality rate was observed
indomethacin depends on the size of among infants receiving prolonged Factors Affecting Ductal
the dose and the number of doses indomethacin. In summary, al- Reopening
administered. Because the plasma though use of a prolonged low-dose Several studies have shown that the
clearance of indomethacin depends indomethacin course is controversial, more immature infant has a greater
on the infant’s postnatal age, a dos- an initial standard three-dose course chance of ductus reopening. Animal
age regimen recommended for in- followed by an additional course may studies have shown that vasa vasorum
fants at the end of the first postnatal be therapeutically advantageous in are less well developed in the preterm
week (when the half-life is 21 h) may preventing reopening of a PDA in ductus compared with the term duc-
lead to elevated plasma concentra- very low-birthweight infants of less tus. Although the reduction in lu-
tions when used in infants on day 1 than 28 weeks’ gestation. men area in preterm animals is similar
(when the half-life is 71 h). to that seen in 1- and 2-day-old term
In addition to its effects on the Timing of Treatment animals, the increase in thickness of
ductus, indomethacin also is associ- The effectiveness of indomethacin in the avascular ductus wall (0.47 to
ated with vasoconstriction of cere- permanently closing the ductus is a 0.67 mm) is only one third of that
bral, renal, and mesenteric vascular function of the infant’s postnatal age seen at term. As a result, the diffusion
beds. Indomethacin causes reduction at the start of treatment. Indometh- path for oxygen is much less in the
in cerebral blood flow (CBF) and acin is more effective when used dur- preterm ductus than it is at term.
CBF velocity ranging from 25% to ing the first days after birth than Consequently, the immature ductus
60%. Prolonging the rate of indo- when used several days later. This is seems to be more resistant to devel-
methacin infusion (20 to 30 min) consistent with studies that demon- oping hypoxia during postnatal con-
alleviates some of the decrease in strate a waning role of PGs in main- striction. Without this hypoxic stim-
CBF, but it does not totally eliminate taining ductal patency with ad- ulus, there is neither cell death nor
the reduction in CBF velocity. vancing postnatal age. Prophylactic vessel remodeling, making the vessel
A continuous indomethacin infusion indomethacin treatment within the more susceptible to later reopening.
(17 mcg/kg per hour over 36 h) of first 15 hours after birth leads to a If the preterm ductus has complete
the same total daily dose appears to higher rate of permanent ductal clo- obstruction of luminal blood flow, it
eliminate any reduction in CBF ve- sure, primarily by causing a greater can develop the same degree of hyp-
locity and decrease its adverse effects degree of initial ductal constriction. oxia as found at term. This under-
further. Renal vasoconstriction also It does not affect the remodeling scores the critical importance of the
has been eliminated by continuous process or alter the inverse relation- initial constrictive phase of ductus
infusion. ship between infant maturity and closure in triggering the subsequent
subsequent reopening. steps of ductus remodeling.
Duration Although prophylactic indometh- Posttreatment echocardiography
PG production is suppressed only acin reduces the chances of develop- with Doppler seems to be the most
transiently following indomethacin ing a symptomatic PDA and the need useful test for predicting ductal re-
therapy. Circulating PGE2 concen- for surgical ligation, it does not ap- opening. If no evidence of luminal
trations return to the normal range pear to offer any additional advan- patency is found on the Doppler
within 6 to 7 days of completing tage in reducing pulmonary mor- study, the chance of later reopening
therapy. This interval may not allow bidity or necrotizing enterocolitis is less than 20% in infants younger
sufficient time for ductal remodeling compared with an approach that than 27 weeks’ gestation. However,
in the most immature infants. A pro- waits for the first symptoms of a PDA if any evidence of luminal patency is
longed maintenance course of low- to appear (around day 3) before ini- found, more than 90% of infants
dose indomethacin (0.1 mg/kg ev- tiating treatment. Because prophy- eventually reopen their ductus. Mak-
ery 24 h for 5 to 7 d) appears both to lactic indomethacin has been shown ing distinctions in the amount of lu-
increase the success of the initial clo- to reduce the incidence of grade minal flow is not important because
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4. pharmacology reviews
even intermittent, clinically insignifi- transient decrease in the urine output Ibuprofen appears to be effective in
cant degrees of luminal blood flow after the overdose. It is interesting to mediating ductal closure while possi-
uniformly are associated with ductal note that there was a 10-fold differ- bly causing less vascular compromise.
reopening. ence in dosage between the two It does not appear to reduce mesen-
groups that initially reported the use teric blood flow, and it has a smaller
Complications of of indomethacin for PDA closure in effect than indomethacin on renal
Indomethacin Treatment 1976, with little difference in adverse perfusion. Ibuprofen does not re-
Most infants treated with indometh- effects. duce CBF and even may extend the
acin develop a transient decrease in range of blood pressures for which
glomerular filtration rate, urine out- Concurrent Use of CBF is autoregulated. Studies in an-
put, fractional excretion of sodium Furosemide imals suggest that ibuprofen may
and chloride, and serum sodium con- Because furosemide increases PG have cytoprotective effects in the in-
centration. Many centers do not use production, it has the potential to testinal tract.
indomethacin if the serum creatinine help prevent indomethacin-related Ibuprofen is administered intrave-
is above 1.2 to 1.7 mg/dL (106.1 to toxicity, but it also could decrease nously at a dose of 10 mg/kg, fol-
150.3 mcmol/L) or if the urine out- ductal response to indomethacin. lowed at 24-hour intervals by two
put is less than 1 mL/kg per hour. Consequently, furosemide may have doses of 5 mg/kg each. Several re-
The reasoning behind this caveat is conflicting physiologic effects in the cently published controlled, ran-
that indomethacin may decrease the preterm infant who has PDA. A re- domized trials have compared the
urine output further and cause signif- cent Cochrane review reported that safety and efficacy of ibuprofen with
icant water and electrolyte problems. there was insufficient evidence to indomethacin in closing a PDA in
A critical value of serum creatinine is support the administration of furo- preterm infants who had RDS. Ibu-
not available. semide to preterm infants treated profen had less of an effect on urine
Indomethacin, in adequate doses, with indomethacin for symptomatic output and fluid retention than did
inhibits platelets and prolongs the PDA. Furosemide appears to be con- indomethacin, but it had a similar
bleeding time. This effect lasts 7 to traindicated in the presence of dehy- effect on ductal closure. Ibuprofen
9 days, until the affected platelets are dration in these infants. also had less of an effect on mesen-
replaced by new ones not exposed to teric blood flow velocity compared
indomethacin. Frank renal or gastro- Prenatal PG Inhibition and with indomethacin. There was no
intestinal bleeding are contraindica- the Ductus difference between the two groups in
tions to the use of indomethacin. Indomethacin has been used as a to- the onset of enteral feedings, rate of
Isolated cases of localized intesti- colytic because PGs play a role in weight gain, or incidence of necro-
nal perforation following indometh- uterine contractility. However, indo- tizing enterocolitis. Nor was there a
acin treatment have been described, methacin readily crosses the placenta difference in the rate of intracranial
but an increased frequency of this and may inhibit fetal PG synthesis. hemorrhage or periventricular leu-
lesion has not been observed in any Although fetal ductus constriction komalacia between the two groups.
of the controlled treatment trials. may occur in as many as 60% of fe- In contrast to the previously cited
The National Collaborative study tuses exposed to indomethacin in information, some animal studies
did observe an increased incidence of utero, these same infants have a have shown that ibuprofen and indo-
occult blood loss from the gastroin- higher incidence of persistent PDA methacin cause similar decreases in
testinal tract (Gersony and associ- postnatally. Indomethacin produces renal blood flow. Speziale and col-
ates), but there was no increased in- constriction and ischemic hypoxia of leagues reported that both indo-
cidence of necrotizing enterocolitis, the fetal ductus, which impairs the methacin and ibuprofen significantly
retinopathy of prematurity, or sepsis. future ability of the ductus to con- increased renal vascular resistance in
A recent report of four infants strict after birth. newborn piglets. Chamaa and associ-
weighing less than 1,000 g at birth ates demonstrated in newborn rab-
who received a 10-fold overdose of Ibuprofen bits that intravenous ibuprofen
indomethacin found no evidence of Ibuprofen, another nonselective caused a dose-dependent, significant
major morbidity; 50% had a transient COX inhibitor, is emerging rapidly reduction in urine volume, glomeru-
increase in serum creatinine and as a potential alternative to indo- lar filtration rate, and renal blood
blood urea nitrogen and 75% had a methacin in the treatment of PDA. flow; a decrease in filtration fraction;
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a steep increase in renal vascular re- therapeutic approach may offer hope Brion LP, Campbell DE. Furosemide for
sistance; and a decrease in urinary in the future for immature infants symptomatic patent ductus arteriosus
in indomethacin-treated infants.
sodium excretion. whose ductus fails to remodel after
CD001148. The Cochrane Library; Ox-
Cooper-Peel and coworkers have indomethacin therapy. ford, England: Update Software 2000
raised questions concerning a possi- Burnard ED. The cardiac murmur in rela-
ble undesirable adverse effect of Selective COX Inhibitors tion to symptoms in the newborn. Br
ibuprofen. They demonstrated that Two isoforms of COX have been de- Med J. 1939;1:134
Clyman RI. Medical treatment of patent
ibuprofen serum concentrations scribed. COX-1 is expressed consti-
ductus arteriosus in premature infants.
achieved during current dosing regi- tutively by most tissues and seems to In: Long WA, ed. Fetal and Neonatal
mens can increase the free fraction of be responsible for the majority of PG Cardiology. 1st ed. Philadelphia, Pa: WB
bilirubin by a factor of four. In con- production in the adult. COX-2 is an Saunders; 1990:682– 690
trast, at therapeutic indomethacin inducible form of the enzyme that Chamaa NS, Mosig D, Drukker A, Guig-
nard JP. The renal hemodynamic effects
concentrations, there is no measur- is stimulated by proinflammatory
of ibuprofen in the newborn rabbit. Pe-
able displacement of bilirubin from agents. Animal studies have shown diatr Res. 2000;48:600 – 605
albumin. Ibuprofen may increase the that both isoforms of COX are ex- Clyman RI, Chan CY, Mauray F, et al. Per-
risk of bilirubin encephalopathy pressed in the fetal and neonatal duc- manent anatomic closure of the ductus
when used in sick preterm infants. tus. Therefore, the applicability of arteriosus in newborn baboons: the roles
of postnatal constriction, hypoxia and
The use of prophylactic ibuprofen selective COX inhibition to the treat-
gestation. Pediatr Res. 1999;45:19 –29
has been found to be as effective as ment of PDA does not seem to be Clyman RI, Chen YQ, Chemtob S, et al. In
prophylactic indomethacin, with no very promising at the moment. utero remodeling of the fetal lamb duc-
significant difference in the incidence tus arteriosus: the role of antenatal indo-
of adverse effects between the two PGE2 Receptor Manipulation methacin and avascular zone thickness
on vaso vasorum proliferation, neoin-
agents. The vascular effects of prostaglandins
tima formation, and cell death. Circula-
are mediated by specific prostanoid tion. 2001;103:1806 –1812
Other Agents receptors. Manipulating these recep- Clyman RI, Narayanan M. Patent ductus
Mefenamic acid is an anthranilic acid tors with agonists and antagonists arteriosus: a physiologic basis for current
derivative that both inhibits PG syn- may offer interesting avenues for fu- treatment practices. In: Hansen TN,
McIntosh N, eds. Current Topics in Neo-
thesis and reduces PG activity, possi- ture therapeutic investigations.
natology Number 4. London, England:
bly by blocking PG receptors. How- WB Saunders, Harcourt Publishers Lim-
ever, it appears to be associated with Conclusion ited; 2000:72–91
more serious gastrointestinal adverse Future studies will focus on the po- Clyman RI, Waleh N, Black SM, Riemer
effects than some of the other non- tential role of combination treatment KR, Mauray F, Chen YQ. Regulation of
ductus arteriosus patency by nitric oxide
steroidal anti-inflammatory agents. with indomethacin and NO inhibi-
in fetal lambs: the role of gestation, ox-
Aspirin (acetylsalicylic acid) had tion, the use of PG receptor antago- ygen tension and vasa vasorum. Pediatr
been considered as an alternative to nists, and manipulation of mediators Res. 1998;43:633– 644
indomethacin treatment of PDA. of vascular remodeling to produce Cooper-Peel C, Brodersen R, Robertson A.
However, at the doses used, it ap- permanent ductus closure. Recent Does ibuprofen affect bilirubin-albumin
binding in newborn infant serum? Phar-
pears to be less effective than indo- studies have shown that ibuprofen
macol Toxicol. 1996;79:297–299
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PDA in infants who have decreased Vangi V, Rubaltelli FF. Prophylaxis of
Future Directions renal function. However, potential patent ductus arteriosus with ibuprofen
NO Inhibition problems arising from its interaction in preterm infants. Acta Paediatr. 2000;
89:1369 –1374
Recent studies in preterm animals with bilirubin and albumin will need
Gersony WM, Peckham GJ, Ellison RC,
and humans have shown that al- to be avoided. Miettinen OS, Nadas AS. Effects of in-
though indomethacin may not con- domethacin in premature infants with
strict the premature ductus suffi- patent ductus arteriosus: results of a na-
ciently to develop tissue hypoxia, a Suggested Reading tional collaborative study. J Pediatr.
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Hammerman C, Glaser J, Schimmel MS, et patent ductus arteriosus: a randomized indomethacin therapy. Pediatrics. 2002;
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NeoReviews Quiz
3. Several factors contribute to the regulation of patency of the ductus arteriosus in the fetus and the
newborn. Of the following, the most accurate statement regarding ductal patency is that:
A. Advancing postnatal age reduces the effect of vasodilating prostaglandins in maintaining ductal
patency.
B. All three isoforms of nitric oxide synthase are located in the ductal wall.
C. Exogenous surfactant treatment promotes constriction of the ductus.
D. Preterm neonates require lesser ductal constriction than term infants to produce ductal wall hypoxia.
E. The zone of ischemic hypoxia in the muscle media of the ductus is larger in preterm than in term
neonates.
4. Indomethacin, a nonselective cyclooxygenase inhibitor, is effective in mediating closure of the ductus
arteriosus in preterm neonates. Of the following, the most accurate statement regarding indomethacin use
is that:
A. A single dose of indomethacin results in persistent constriction of the ductus.
B. Circulating prostaglandin E2 concentration returns to normal within 24 hours of indomethacin
treatment.
C. Indomethacin is more effective when used during the first few days after birth than later.
D. Prolonged infusion of indomethacin eliminates any reduction of cerebral blood flow.
E. The half-life of indomethacin is positively related to postnatal age.
5. Prophylactic administration of indomethacin reduces the occurrence of symptomatic patent ductus
arteriosus and the need for surgical ligation of the ductus in preterm neonates, and it may have other
beneficial effects. Of the following, prophylactic indomethacin treatment is most likely to reduce the
incidence of:
A. Chronic lung disease.
B. Disseminated intravascular coagulopathy.
C. Intraventricular hemorrhage.
D. Necrotizing enterocolitis.
E. Retinopathy of prematurity.
6. Ibuprofen, a nonselective cyclooxygenase inhibitor, is emerging as a potential alternative to indomethacin in
the treatment of patent ductus arteriosus in preterm neonates. Of the following, the potential risk most
associated with ibuprofen treatment is:
A. Bilirubin encephalopathy.
B. Gastrointestinal perforation.
C. Intraventricular hemorrhage.
D. Periventricular leukomalacia.
E. Renal failure.
NeoReviews Vol.4 No.8 August 2003 e221