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Patent ductus arteriosus: Pathophysiology and management

Article  in  Journal of Perinatology · June 2006

DOI: 10.1038/sj.jp.7211465 · Source: PubMed

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 Journal of Perinatology (2006) 26, S14–S18
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ORIGINAL ARTICLE
Patent ductus arteriosus: pathophysiology and management
ER Hermes-DeSantis1 and RI Clyman2
1
Drug Information Service, Robert Wood Johnson University Hospital, Ernest Mario School of Pharmacy, Rutgers, The State University
of New Jersey, New Jersey, USA and 2Cardiovascular Research Institute, Department of Pediatrics, University of California, San
Francisco, San Francisco, CA, USA

management of these patients. Animal models have helped to

Patent ductus arteriosus (PDA) in preterm newborns prior to 28 weeks of unravel the pathophysiology of the PDA and to understand the
gestation has led to many challenges regarding the type and timing of factors responsible for its closure or patency after birth. The
treatment regimens. A PDA results in increased pulmonary blood flow and appropriate timing of prostaglandin (PG) inhibitors, such as
redistribution of flow to other organs. Several co-morbidities (i.e., indomethacin, is another area of debate. There is concern about
necrotizing enterocolitis, intracranial hemorrhage, pulmonary edema/ early prophylaxis with indomethacin since some infants might be
hemorrhage, bronchopulmonary dysplasia, and retinopathy) are associated exposed to an unnecessary agent if the ductus would have closed
with the presence of a PDA, but whether or not a PDA is responsible for their on its own. On the other hand, delaying treatment until one can
development is still unclear. The prostaglandin inhibitor, indomethacin, is document that the PDA is unlikely to undergo spontaneous closure
effective in the treatment of PDA. Questions regarding the optimal timing of may increase the infant’s chances of developing morbidities caused
the intervention – early prophylaxis or treatment, once signs and symptoms by the PDA and make the success of pharmacological closure less
become evident – have challenged physicians for decades. Both evidence likely. This article will review both the published evidence and the
and experience are explored in this article. Comparative physiology between experience in the management of PDA.
the full-term and preterm newborn and the barriers preventing the
necessary cascade of events leading to permanent constriction of the PDA
are reviewed.
Journal of Perinatology (2006) 26, S14–S18. doi:10.1038/sj.jp.7211465
Pathophysiology
Keywords: infant; newborn; premature; indomethacin
In utero, low fetal systemic arterial oxygen tension (PaO2) and
elevated circulating PGs (in addition to PGs made within the
ductus wall itself) play a significant role in keeping the lumen of
Introduction
the ductus arteriosus patent. This is necessary for fetal circulation
The ductus arteriosus is an essential component of fetal circulation and survival. After a full-term birth, the ductus closes within 24–
allowing for communication between the pulmonary artery and the 48 h of delivery.2
aorta. After birth, it usually closes within 48 h. A persistently patent The closure of the ductus arteriosus in full-term infants occurs
ductus arteriosus (PDA) is diagnosed when the ductus arteriosus in two steps. Initially, within the first few hours after birth,
fails to close after 72 h.1 Patent ductus arteriosus increases increased arterial PaO2 and decreased circulating PGs allow the
pulmonary blood flow and left atrial and ventricular volumes, and smooth muscle media of the ductus to constrict. As a result of the
produces a redistribution of systemic blood flow. Clinical constriction, the inner muscle wall of the ductus arteriosus
complications are dependent on the degree of left to right shunting develops profound ischemic hypoxia which leads to the formation
through the ductus. Hemodynamic symptoms from a PDA are of vascular endothelial growth factor, transforming growth factor-
present in 55–70% of infants delivered below 1000 g or prior to 28 beta, and other inflammatory mediators and growth factors that
weeks of gestation and may require either medical or surgical transform the ductus into a non-contractile ligament.3
intervention.2 Conversely, in preterm infants, the ductus often fails to constrict
There are various factors that contribute to patency of the in the days following birth. Even in those preterm infants who
ductus arteriosus. Similarly, there are numerous strategies in the achieve ductus constriction, the ductus frequently fails to develop
Correspondence: Dr RI Clyman, Box 0544, HSE-1492 1492, University of California, San the level of profound hypoxic ischemia needed to cause remodeling
Francisco, San Francisco, CA 94143-0544, USA. of the artery. As a result, many premature infants with a closed
E-mail: [email protected] ductus can reopen their ductus and develop clinical symptoms
Disclosure: No significant relationship to disclose. related to the PDA.4
 Patent ductus arteriosus
ER Hermes-DeSantis and RI Clyman
S15

Several endogenous vasodilators made within the ductus wall within the ductus wall. In the premature ductus, even when the
(e.g., PGs and nitric oxide) are known to inhibit ductus closure. lumen of the ductus remains patent, energy metabolites (i.e.,
Among the prostaglandins, PGE2 appears to be the most important glucose, oxygen, and ATP) begin to fall after birth. Although this is
in keeping the ductus patent. Reduction of PG synthesis by not profound enough to cause cell death and remodeling, it does
inhibition of cyclooxygenase (COX) produces constriction of the interfere with the ductus’ ability to contract.6
ductus.1 In addition to PG, nitric oxide is produced by the ductus. It should be noted that even when the premature ductus does
Nitric oxide synthase is found in both the endothelial cells lining constrict, it remains relatively resistant to developing profound
the ductus lumen and in the vasa vasorum that lie in the ductus hypoxia, which is the primary signal driving the cell death and
adventitia. The premature ductus is more sensitive to the effects of inflammatory cascade resulting in remodeling. Although the main
both PGs and nitric oxide. Clinical observations reveal that PG source of nutrients in the ductus is through the lumen, a
inhibitors are more effective if given on the first day after birth and substantial amount is provided by the vasa vasorum, which supply
may be less effective as postnatal age increases. Animal studies to the outer wall of the ductus. The vasa vasorum enter the outer
reveal that nitric oxide production increases in the ductus wall after wall of the ductus and grow toward the lumen. They stop growing
birth and may play a role in the decreasing effectiveness of approximately 400–500 mm from the lumen. The distance between
indomethacin with increasing postnatal age. In both animal and the lumen and the vasa vasorum is called the avascular zone of the
human studies, a combination of indomethacin and nitric oxide vessel. The thickness of the avascular zone (400–500 mm) defines
synthase inhibition, several days after birth, causes more effective the furthest distance that two sources of nutrients can be separated
ductus constriction than indomethacin alone2 (Figure 1). and still maintain oxygen and nutrient homeostasis in the tissue.
There are several other reasons why the PDA may become less In the full-term ductus, the increased tissue pressure occurring
responsive to indomethacin after birth in the preterm infant. during ductus constriction occludes the vasa vasorum and prevents
Shortly after birth, there is an inflammatory response that develops any flow of nutrients to and through the outer wall of the vessel.
within the wall of the ductus arteriosus. This response is associated This results in the ‘effective’ avascular zone expanding from
with the influx of monocytes/macrophages into the ductus wall 500 mm to the entire thickness of the vessel wall (approximately
and the induction of several cytokines such as interferon gamma 1.2 mm). When this occurs, the center of the ductus wall becomes
and tumor necrosis factor-alpha. Several of these cytokines are profoundly ischemic.3
potent vasodilators that act through mechanisms independent of In the premature (24 week gestation) ductus, the vessel wall is
either PGs or nitric oxide.5 only about 200 mm in thickness (Figure 2). The scattered vasa
Another reason for the diminished contractile responsiveness of vasorum in the vessel lie in the adventitia and do not penetrate the
the ductus to indomethacin after birth has to do with energetics muscle media. The thin-walled immature ductus does not need the

Figure 1 Factors involved in the patency of the ductus. PGE2 ¼ prostaglandin E2, PGI2 ¼ prostaglandin I2, NO ¼ nitric oxide, KDR ¼ direct
rectifying voltage-sensitive potassium channel, ATP ¼ adenosine triphosphate, cyt P450 ¼ cytochrome P450, ET-1 ¼ endothelin 1, ETA ¼ endothelin A

Journal of Perinatology
 Patent ductus arteriosus
ER Hermes-DeSantis and RI Clyman
S16

Treatment
Indomethacin (Indocins IV, Merck, West Point, PA, USA) is a PG
inhibitor that has been used for the closure of PDA since the late
1970s. Indomethacin has been utilized as early symptomatic
therapy, late symptomatic therapy, or prophylactic therapy.7
There is still ongoing debate regarding when to treat a PDA in
premature infants who are born before 28 weeks of gestation.
Physicians for decades have weighed the pros and cons of early
prophylactic therapy versus late treatment for infants who are most
at risk for developing complications from a PDA. Clinical
experience reveals that if a delayed treatment approach is used
(waiting until hemodynamic symptoms of a PDA appear), 55–70%
of infants born before 28 weeks of gestation and weighing less than
1000 g at birth ultimately will be treated for a PDA during their
Figure 2 Ductus arteriosus in the fetus and full-term and preterm hospitalization. The evidence suggests that preterm infants require
newborn.
a tighter degree of constriction than full-term infants to develop the
anatomic changes that lead to permanent ductus closure. Even
minimal degrees of ductus patency after indomethacin treatment
vasa vasorum for nutrient flow because it can receive all of its will prevent remodeling and lead to subsequent clinical reopening.
nutrient flow from its lumen. As a result, during closure of the Clinical and laboratory experience also indicates that PG inhibitors
preterm ductus, there is no vulnerable region of the wall that is at given as prophylaxis, early after birth, are more effective in
risk for loss of vasa vasorum flow. Although the avascular zone of producing tight ductus constriction than waiting several days for
the preterm ductus wall thickens slightly after birth, it does not symptoms to develop. The delay of several days may necessitate the
thicken to the extent that occurs at term. As a result, the preterm use of other vasoconstrictive agents, in addition to indomethacin,
ductus arteriosus is less likely to develop the severe degree of to produce the same degree of ductus closure. Preterm infants who
hypoxia that is necessary for ductus remodeling.3 In order for the are born before 28 weeks of gestation and who receive prophylaxis
preterm ductus to develop the degree of ischemia needed to set up with indomethacin by 6–15 h after birth consistently have a lower
the remodeling cascade, it is essential that it develop complete incidence of serious pulmonary hemorrhage, intracranial
luminal obliteration and complete elimination of nutrient flow to hemorrhage (grade III/IV), and need for ductus ligation.8–10
its wall. A platelet count of at least 50 000 is necessary prior to the first
dose of indomethacin. A PT and PTT should be obtained if there is
any concern about bleeding. Serum creatinine and platelet count
Clinical findings and associations should be checked prior to second and third doses. Because of
Patent ductus arteriosus is associated with several neonatal decreased gastrointestinal blood flow secondary to indomethacin,
morbidities. Both animal and human studies have demonstrated the infant is restricted to no oral intake during treatment and for
alterations in blood pressure with a drop in the mean, as well as, 48 h after treatment is completed. Urine output should be
systolic and diastolic pressures. Left ventricular output can increase monitored since the infant may experience a transient decrease in
by as much as 100%. In spite of this increased cardiac output, output requiring alterations in fluid administration. Indomethacin
redistribution in blood flow results in increased flow to the lungs may be restarted when urine output is greater than 1 ml/kg/h.
and decreased flow to the pressure passive organs like the In infants less than 28 weeks gestation, a Doppler exam of the
intestines, skin, muscle, and kidneys. This redistribution may result ductus should be obtained between the second and third
in metabolic acidosis, necrotizing enterocolitis (NEC), and indomethacin dose. If the Doppler study reveals any lumen
pulmonary edema/hemorrhage. patency, even if the vessel is constricted, there is at least an 80%
Timing is important in evaluating when different chance of reopening. In contrast, if the ductus is closed on
morbidities will present. Intracranial hemorrhage usually Doppler, there is less than 15% chance that it will reopen in the
occurs within the first 3 days after birth. Similarly, marked future. Therefore, if there is evidence of ductus patency, regardless
pulmonary edema and pulmonary hemorrhage secondary to of clinical signs, an additional three doses of indomethacin
fluid shifts and ductus patency occurs within 2–3 days (0.1 mg/kg) should be administered at 24 h intervals. This
after birth. Necrotizing enterocolitis usually presents 5 days additional treatment will significantly increase the likelihood of
after birth.7 permanent ductus closure.11 An additional Doppler should be

Journal of Perinatology
 Patent ductus arteriosus
ER Hermes-DeSantis and RI Clyman
S17

Table 1 Contraindications to the administration of indomethacin12 mechanics that result from pulmonary edema, its role in
producing other long-term irreversible pulmonary morbidities, like
Active bleeding
Active or suspected necrotizing enterocolitis
pulmonary remodeling and chronic lung disease, have yet to be
Creatinine X2.0 mg/dl demonstrated. Similarly, its role in the development of NEC is
Urine output <0.6 ml/kg/h based on limited clinical data acquired more than 20 years ago.
Platelet count <50 000 Additional clinical trials should be designed and conducted in order
Active and untreated infection to gather the evidence needed to determine ideal treatment
Suspected congenital heart disease parameters. One approach to evaluate the role of a PDA in
Known gastrointestinal or renal anomaly pulmonary and gastrointestinal morbidities might compare early
prophylaxis with indomethacin to no treatment or delayed
treatment (after 2–3 weeks), when the presence of a moderate
PDA is firmly established and the exposure to the left to right shunt
Table 2 Indomethacin dosing12 is of chronic duration. At that point, the two groups can be
Birth weight Regimen
compared to determine the presence or lack of morbidities, and
whether the ductus or the indomethacin played a role in the
First dose Second dose Third dose outcomes.
Gestational ageX28 weeks, with clinical manifestations of PDA
>1250 g 0.2 mg/kg 0.2 mg/kg 12 h after 0.2 mg/kg 24 h after Conclusions
first dose second dose Patent ductus arteriosus is a significant health risk to the preterm
1000–1250 g 0.2 mg/kg 0.1 mg/kg 12 h after 0.1 mg/kg 24 h after infant. Proper understanding of the mechanisms responsible for its
first dose second dose delayed closure at birth is necessary for better treatment strategies.
The role of indomethacin is well established; however, the best
Gestation <28 weeks, prophylactic 6–15 h after birth timing of therapy to prevent morbidity is still an unanswered
0.2 mg/kg 0.1 mg/kg 24 h after 0.1 mg/kg 24 h after
question.
the first dose the second dose

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subsequent reopening. Table 1 lists the contraindications against treatments for patent ductus arteriosus. Drug Safety 2001; 24: 537–551.
3 Clyman RI, Chan CY, Mauray F, Chen YQ, Cox W, Seidner SR et al.
indomethacin use.
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