Patent Ductus Arteriosus in Preterm Infants,

Part 1: Understanding the Pathophysiologic

Link Between the Patent Ductus
Arteriosus and Clinical Complications
Yasser N. Elsayed, MD, PhD
Debbie Fraser, MN, RNC-NIC

Continuing
Nursing Education
(CNE) Credit
Abstract
Attention Readers: The The clinical guidelines for treating patent ductus arteriosus (PDA) have significantly evolved over
test questions are provided in this the last decades from treating any ductal shunt to more conservative management where only the
issue, but the posttest and evaluation hemodynamically significant patent ductus arteriosus (HSPDA) is treated. This shift has resulted largely
must be completed online. Details to
complete the course are provided online from a lack of evidence from randomized controlled trials supporting a relationship between treating a
at academyonline.org/CNE. A total PDA and improving long-term neonatal outcomes. However, there are many unresolved issues. There
of 1.4 contact hour(s) may be earned
as CNE credit for reading this article
is no consensus on the precise definition of HSPDA requiring treatment or a clear understanding
and completing the online posttest of when to treat HSPDA. Moreover, the current evidence shows worsening of the long-term
and evaluation. To be successful neurodevelopmental outcome for infants undergoing surgical PDA ligation.
the learner must obtain a grade of
at least 80% on the test. Test expires The presence of physiologic variability among preterm infants, and the presence of different
three (3) years from publication date. compensatory mechanisms may make it difficult to establish a link between pathophysiology and long-
Disclosure: The authors/planning term outcomes. That is, the physiologic variability cannot be simply assessed by randomly assigning
committee have no relevant financial
interest or affiliations with any infants into two arms of a study. Relying on research from animal and human studies, this article
commercial interests related to the explains the link between the pathophysiology of a PDA and neonatal outcomes.
subjects discussed within this article.
No commercial support or sponsorship
was provided for this educational Keywords: patent ductus arteriosus; neonatal pathophysiology; preterm infants; neonatal outcomes
activity. ANN/ANCC does not
endorse any commercial products
discussed/displayed in conjunction
with this educational activity.
The Academy of Neonatal Nursing is
accredited as a provider of continuing

P
nursing education by the American
Nurses Credentialing Center ’s
Commission on Accreditation.
Provider, Academy of Neonatal
atent ductus arteriosus (PDA) is the changes with subsequent end-organ and auto-
Nursing, approved by the California most common cardiovascular problem regulatory compensatory mechanisms that are
B oard of R egis tered Nursing,
Provider #CEP 6261; and Florida
in preterm neonates, with an incidence as high indirectly linked to widely variable short- and
Board of Nursing, Provider #FBN as 33 percent in infants ,31 weeks’ gesta- long-term morbidities.3–5 The complications
3218, content code 2505.
tion, and is associated with variable degrees are more related to the magnitude of left-to-
The purpose of this article is to
examine the pathophysiology of a
of short- and long-term adverse outcomes.1 right shunt volume across the PDA, rather than
patent ductus arteriosus (PDA) Considering the complications of both merely its patency.6,7 Although the volume of
in o rd e r t o a s s i s t re a d e r s in medical and surgical PDA, treatment and the shunt is hard to calculate directly, using
understanding the hemodynamic
effects of PDA. This knowledge forms determining which infants to treat and when echocardiography, surrogate clinical markers,
the basis of understanding how to to treat to minimize PDA-related morbidity biochemical and tissue oxygenation markers
gauge the significance of the PDA
and ultimately, determining which remains challenging for neonatal health care of pulmonary overcirculation, and systemic
infants may benefit from treatment. providers.2 The hemodynamic effects of a PDA hypoperfusion can provide clues to the mag-
are not as simple as postnatal patency of a fetal nitude and consequences of the shunt.8–10 By
channel; there are a series of acute physiologic examining the pathophysiology of a PDA,
Accepted for publication
May 2017.

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 this article will assist readers in understanding the hemo-
dynamic effects of PDA. This knowledge forms the basis of
understanding how to gauge the significance of the patent
ductus arteriosus and ultimately, determining which infants
may benefit from treatment.
PERINATAL HEMODYNAMICS OF PDA
Role of Ductus Arteriosus in the Fetal Hemodynamics
In utero, oxygenated blood returns from placenta to the
fetus via the umbilical vein where it is directed, in part,
through the ductus venosus to join the inferior vena cava
(IVC). To supply the needs of the brain, this oxygen-rich
blood is preferentially directed through the foramen ovale
into the left heart, which pumps this blood to the upper body
(brain) through the left ventricle. The less oxygenated blood
from the liver and superior vena cava (SVC) is directed into
the right heart. The output from the right ventricle is shunted
across the ductus arteriosus from the pulmonary artery to
the descending aorta, bypassing the lungs. Because of the
high pulmonary vascular resistance, ,20 percent of the fetal
cardiac output enters the fetal lungs.10 The combined cardiac
output of the fetal heart is around 450 ml/kg/minute with
increasing right ventricular dominance through the second
and third trimester. In utero, the shunt across the ductus
arteriosus is right to left because of high pulmonary pres-
sure in the fetal lung.11,12 Figure 1 demonstrates antenatal
hemodynamics of PDA.
PDA and Transitional Circulation in Preterm Infants
Postnatal cardiovascular adaptation is a complex process
moving from parallel fetal circuits of circulation to an inte-
grated postnatal pulmonary and systemic circulatory pathway.
Once the lung starts to function for gas exchange and
PaO2 begins to rise, pulmonary vascular resistance begins
to drop, followed by gradual closure of fetal shunts (PDA
and patent foramen ovale) —within 48 hours in most term
and late preterm infants.12 Closure of the PDA results from
FIGURE 1 ■ Role of the ductus in fetal circulation.
High pulmonary vascular resistance Low systemic vascular resistance
Ductus is shunting right
(pulmonary) to left (systemic)
High biventricular cardiac output
almost solely directed to systemic
and only 10% to pulmonary circulation
High fetal cardiac output is
important to compensate for low
(antenatal) oxygen saturation
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increased arterial oxygen tension (vasoconstrictor effect) and
decreased placental prostaglandins (vasodilator effect). The
sensitivity of preterm infants to these agents is incomplete or
impaired. In preterm infants, these shunts frequently remain
open and complicate already compromised hemodynamics
and autoregulatory mechanisms.12,13 Systemic vascular resis-
tance increases after removal of the low resistance placental
circulation, a change which is usually well tolerated in term
and late preterm infants. In very premature or very low birth
weight (VLBW) infants, this change in systemic vascular
resistance can result in impaired cardiac output because it
increases the afterload of the myocardium. Unlike the intra-
uterine environment where cardiac output comes from both
ventricles, systemic postnatal circulation relies on output from
the left ventricle alone. Systemic flow can be further compro-
mised if the ductus arteriosus remains open, allowing shunt-
ing from left to the right, shifting more blood away from
systemic flow to recirculate within the pulmonary circulation.
Systemic compromise can be more complex in the presence
of poor autoregulation of cerebral blood flow during the first
12–36 hours after birth. Autoregulation gradually improves
over the first three days of life.12,13 Figure 2 summarizes the
hemodynamic effects of PDA in early postnatal circulation.
For a long time, it was thought that the brain was assigned
as a vital organ with a highly protective autoregulatory mech-
anism. Current animal research work has shown that, in fact,
in addition to the heart and adrenal gland, only the hindbrain
is protected.14 This makes the forebrain vulnerable to postna-
tal white matter damage. Improvement of cerebral autoreg-
ulation, which occurs around 48–72 hours after birth, and
reperfusion of the brain parenchyma with increased cerebral
blood flow may cause bleeding in the fragile choroid plexus
leading to intraventricular hemorrhage (IVH).13 Figure 3
shows the effect of PDA on the development of IVH.
FACTORS AFFECTING HEMODYNAMIC
SIGNIFICANCE OF PDA
Determining the hemodynamic significance of a PDA is more
complex than equating the larger the size of the ductus with
clinical compromise. Many factors affect the volume of blood
moving through the ductus,6 including postnatal age and under-
lying medical conditions. Other factors include the following:
• Size and shape of the PDA: This is the most important
factor. A larger tube typically allows increased blood flow.
The shape is another contributing factor because a shorter
and less tortuous ductus shunts more blood. A ductus may
also be S shaped or have a sharp angle; this may limit flow
through it.15
• Vascular resistance: Vascular resistance on either side of the
ductus (systemic or pulmonary) is the second most impor-
tant factor and is the only factor that determines the direc-
tion of the blood flow.16 Vascular resistance is the most
dynamic factor and is time-related. Vascular resistance will
be discussed in more detail below.
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 FIGURE 2 ■ Early postnatal transition and the role of patent ductus arteriosus (PDA) in preterm infants.

Decrease pulmonary vascular Removal of low resistance

resistance after spontaneous placental circulation
breathing

Increase pulmonary blood flow after lung

inflation
surfactant if given and with higher oxygen Increase systemic vascular resistance
tension

PDA is shunting left to Potential myocardial dysfunction

right

Low systemic bloodflow

Decompensated with:
Compensated and
hypotension-lactic
asymptomatic
acidosis-oliguria

• Chemical mediators: The muscular layer of the PDA is
responsive to various chemical and biological mediators
under both stable and disease conditions. Oxygen and oxi-
dative stresses, cytokines, and circulating prostaglandins
are examples of theses mediators.17
• The viscosity of the blood: Less viscous blood, for example, in
infants with anemia, results in a greater left-to-right shunt,
whereas less shunting occurs with polycythemia.
NATURAL HISTORY OF VASCULAR
RESISTANCE CHANGES IN
PRETERM INFANTS
Pulmonary artery pressure drops after birth because
of inflation of the lung and an increase in arterial oxygen
tension. In the presence of a PDA, the decline in pulmonary
artery pressure and the associated increase in systemic vas-
cular resistance results in a change in the direction of blood

FIGURE 3 ■  ow intraventricular hemorrhage develops in preterm infants, typically when fragile vessels of the germinal matrix are
H
exposed to increased blood flow as a result of cerebral reperfusion.

Early postnatal transition with Late postnatal transition with

low CBF improved CBF and
Poor autoregulation autoregulation
(hypo perfusion stage) (reperfusion stage)

Sagittal section of brain before IVH Sagittal section of brain with bilateral grade IV IVH

Abbreviations: CBF 5 cerebral blood flow; IVH 5 intraventricular hemorrhage.

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Factors that Alter Pulmonary
Vascular Resistance
Factors which decrease pulmonary vascular resistance
• Hyperoxia
• Hyperventilation
• Alkalosis
• Pulmonary vasodilators (such as inhaled nitric oxide,
milrinone, prostacyclin, and sildenafil)
Factors which increase systemic vascular resistance
• Use of vasopressor medications such as norepinephrine
or vasopressin may increase systemic vascular resistance
and increase the magnitude of left-to-right shunt. On
the other hand, use of systemic vasodilators such as
high doses of dobutamine or magnesium sulfate may
lower systemic resistance and decrease the magnitude
of left-to-right shunt; however this can further
compromise systemic blood flow.
flow across the ductus. When right-sided heart pressures are
higher, the flow across the ductus moves from right-to-left
(pulmonary to systemic). Factors that alter pulmonary vas-
cular resistance are outlined in the sidebar. Because the left
ventricle begins to generate higher pressures, there is a shift
in blood flow resulting in a left-to-right shunt that may com-
promise the systemic blood flow.18 Moreover, because of sub-
optimal autoregulation in the first 12–24 hours after birth,
changes in blood flow across the ductus may aggravate the
transient pressure-passive blood flow to the brain.16
If the PDA remains open beyond first 72 hours of life,
increased blood flow from the systemic to the pulmonary cir-
culation may result in pulmonary edema. A significant amount
of the left ventricular output moves through the PDA to the
lungs and back to the left side of the heart causing dilation of
the left heart and resulting in cardiomegaly and pulmonary
edema.19 The infant may demonstrate signs of heart failure
and require continued or increasing respiratory support. In
the face of increased pulmonary blood flow, pulmonary vas-
cular resistance begins to gradually increase over an extended
time and can continue years after birth. Increased pulmo-
nary resistance will eventually begin to reverse the direction
of the shunt leading to a back up of pressure in the right
heart. Over time, this will result in development of irrevers-
ible pulmonary hypertension (Eisenmenger syndrome); the
infant or child will develop cyanosis and right-sided heart
failure.20
CLINICAL CONSEQUENCES OF A
LEFT-TO-RIGHT PDA SHUNT
After a period of normal postnatal transition, pulmonary
artery pressure decreases resulting in increased pulmonary
blood flow.21 If the PDA persists or medical closure fails, the
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pulmonary circulation will continue to increase, reaching
as much as double or triple the systemic circulation instead
of maintaining the normal ratio of pulmonary-to-systemic
blood flow in the newborn of 0.8:1.2.22,23
Effects of Overcirculation on the Lungs
The balance between the volume of pulmonary circu-
lation and alveolar ventilation is normally maintained in
equity to ensure a physiologic matching of gas exchange and
pulmonary circulation. In other words, each functioning
alveolus should be ventilated and surrounded by a perfused
capillary. This state of balance is expressed as a ventilation–
perfusion (V/Q) match. Pulmonary overcirculation with
resulting edema can reduce the alveolar surface area for gas
exchange, resulting in V/Q mismatch.10 This V/Q mis-
match will be demonstrated by variable degrees of hypox-
emia and hypoventilation and increasing need for respiratory
support.8,24 In these infants, the chest x-ray shows cardio-
megaly, an obtuse angle between the left and right tracheal
bifurcation that is caused by left atrial dilation, with a con-
gested lung field (Figure 4).
Higher pulmonary vascular resistance is a protective
mechanism which reduces the pressure on fragile alveolar
capillary membranes, thereby reducing the risk of pulmo-
nary hemorrhage. Pulmonary overcirculation may lead to
acute pulmonary hemorrhage with the greatest period of risk
being the first seven days after birth in preterm infants born
at ,29 weeks’ gestational age.25
Failure of ductal closure may lead to prolonged ventila-
tion and longer exposure to oxygen therapy. These, in turn,
FIGURE 4  hest x-ray of infant born at 24 weeks, postnatal age
C
■
6 weeks, shows cardiomegaly and congested lung
fields because of large patent ductus arteriosus.
This x-ray was taken one day before patent ductus arteriosus (PDA)
ligation.
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 can cause continued lung injury with impaired alveolization.
Prolonged ventilation increases the risk for prolonged hos-
pitalization, ventilator-associated pneumonia, and other
infections. 26 Long-term exposure of the lungs to over-
circulation may predispose to the infant to chronic lung
changes and bronchopulmonary dysplasia (BPD). Recent
evidence suggests that early evaluation of the PDA may
assist in predicting the risk of BPD. 27 In a large multicenter
study, hemodynamically signif icant patent ductus arte-
riosus (HSPDA) in preterm infants was associated with
increased risk of chronic lung disease, regardless of the
time of closure, with an odds ratio of 1.9. 28 However, no
treatment modality for PDA has been shown to prevent
chronic lung disease. 29–31
SYSTEMIC CONSEQUENCES OF
LEFT-TO-RIGHT PDA SHUNT
Diverting or stealing blood f low from the systemic to
pulmonary circulation may lead to decreased blood flow to
body organs such as the gut and the kidneys. Compromised
systemic perfusion is greater during the diastolic phase of
circulation, and the effect of diminished blood flow on the
organs depends on the organs’ intrinsic capacities to com-
pensate for decreased blood flow through autoregulation.
Because autoregulation improves after birth, the effects of
a PDA on the brain and on myocardial perfusion may be
lessened.32 Systemic signs of PDA may include hypotension,
especially affecting the diastolic pressure; metabolic acidosis;
and oliguria.9
HSPDA and Necrotizing Enterocolitis
Research has shown an increased risk of necrotizing
enterocolitis (NEC) in the presence of a PDA. In fact, a PDA
is an independent risk factor for NEC with an odds ratio of
1.8.33 Again, prophylactic or rescue treatment of the PDA
has not been shown to decrease the incidence of NEC.34,35
A case series showed the development of NEC after blood
transfusion in cases with significant PDA; we speculate that
exposure of the gut to reperfusion–reoxygenation injury may
explain transfusion-associated NEC in preterm infants with
PDA.36 In infants with a PDA, stealing of blood during dias-
tole may compromise intestinal perfusion causing ischemic
hypoperfusion. Transfusion may then induce reperfusion
injury of the gut, leading to NEC.33
HSPDA and Renal Impairment
Increased left-to-right blood flow through a PDA during
diastole may cause renal failure secondary to hypoperfusion.
Signs of renal failure include increased creatinine, hypona-
tremia, and oliguria. Activation of the renin–angiotensin–
aldosterone system may aggravate both renal and heart failure.37
Volume overload of the left heart can increase the serum level
of B-type natriuretic peptide (BNP). B-type natriuretic peptide
has a compensatory vasodilator and diuretic effect.38 Failure of
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compensatory and autoregulatory mechanisms further induce
renal damage and cause end organ failure.39
HSPDA and Cardiac Performance
Volume overload of the left heart with HSPDA causes
diastolic dysfunction which can be detected by Doppler
evaluation of mitral, pulmonary veins, and tissue Doppler
indices. 27 The systolic function may be normal or hyper-
dynamic with increased fractional shortening and high
left cardiac output.40 In the presence of high left cardiac
output, more blood is diverted across the PDA from the
systemic circulation to the pulmonary circulation resulting
in pulmonary edema and further compromise to the sys-
temic circulation.18,41–43 In some cases, myocardial decom-
pensation results in the need for inotropic support. Cardiac
decompensation has also been reported after PDA ligation
and has been attributed to factors such as a sudden increase
in afterload and decrease in preload, exposure to anesthesia,
and adrenal dysfunction.44,45
HSPDA and Neurodevelopment
In the longer term, neurodevelopmental delay is the most
challenging outcome that needs to be addressed. Long-term
exposure of white matter to compromised blood flow from
a PDA may lead to injury which affects neuronal develop-
ment.13,18,46 In spite of this plausible relationship between
PDA and neurodevelopment, there are no randomized, con-
trolled trials showing that either prophylaxis or treatment
improves long-term outcomes.35,47,48
RISKS OF TREATING A PDA
Aggressive treatment of HSPDA has been associated with
increased morbidity and mortality. In an analysis of PDA
management done over a five-year period by the Canadian
Neonatal Network, PDA ligation was associated with an
increased risk of NEC (Stages 2 and 3), ROP (Stages 3, 4,
and 5), and BPD when compared to medical treatment or
conservative management.47 Any treatment strategy must
balance the risk of shunt on hemodynamics and the impact
of treatment.
THE EFFECT OF A PDA ON
NEONATAL OUTCOME
The relationship between PDA and outcomes cannot be
viewed as a direct causal relationship. There are two main
pathophysiologic pathways that can cause cellular compro-
mise and lead to long-term unfavorable outcomes in neo-
nates. These pathways include compromised blood f low
and oxygen homeostasis which initiates an inf lammatory
process and any respiratory condition that disturbs oxygen
homeostasis. There is an overlap between these two pathways
(Figure 5).49–52 All preterm infants are exposed to variable
degrees and multiple causes of inflammation and disturbed
269
8/12/17 5:56 PM
 FIGURE 5 ■ The complex relationship between different risk factors of prematurity and outcomes.

Oxidative Infections
PDA NEC Hypoxia
stress
1
Circulatory
failure
and reperfusion
injury
2
React ry
ive ox y inju
ygen s mator
3 Proo pecie
s Inflam atory
xida
nt Apoptosis inflamm
Anti-
Anti atory
Med
iator oxid flamm Mediators
s a nt Proin

4 Retinopathy of Chronic lung Neurodevelopment

prematurity disease delay

These risk factors including patent ductus arteriosus (PDA) (row 1) may predispose to the three major long-term complications (row 4) through
two common overlapping pathways: inflammatory injury and reactive tissue oxygen species (row 2). Inflammatory injury results from increased
release of proinflammatory mediators without sufficient compensatory effect of anti-inflammatory mediators. Reactive oxygen species may
damage neuronal and lung tissues if prooxidants exceed antioxidants.
Abbreviation: NEC 5 necrotizing enterocolitis.

oxygen homeostasis including lung disease, HSPDA, infec-
tions, and NEC.9 Therefore, it becomes difficult to directly
determine the contribution of a HSPDA to long-term
outcomes.
SUMMARY
HSPDA has a significant effect on both pulmonary and
systemic circulations, which, in turn, impacts both short- and
long-term outcomes. In utero, the ductus arteriosus plays an
important role in the distribution of cardiac output. After
birth, ongoing ductal patency impacts blood flow to several
organs including the brain, heart, lungs, and kidneys. Altered
blood flow to these organs has the potential to impact short-
and long-term clinical outcomes. Through a better under-
standing of the impact of the PDA on hemodynamics in
preterm infants, it is possible to develop a systematic approach
to assessing the impact of these changes on individual organs
and to better target those neonates for whom treatment is
warranted.
10. Lakshminrusimha S, Saugstad OD. The fetal circulation, pathophysiology
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2015;1610:51-60. http://dx.doi.org/10.1016/j.brainres.2015.03.021 New Hanover Regional Medical Center in
Wilmington, North Carolina offers opportunities
for nurses to increase their knowledge
About the Authors and advance their careers.
Yasser N. Elsayed, MD, PhD, is an assistant professor of Pediatrics
and Child Health, Faculty of Health Sciences, College of Medicine,
University of Manitoba, Canada; staff neonatologist of Health
Sciences Centre, Winnipeg; and director of the Targeted Neonatal
Echocardiography and Hemodynamics program.
Experienced
Debbie Fraser, MN, RNC-NIC, is an associate professor and the
director of the Nurse Practitioner program in the Faculty of Health
Disciplines at Athabasca University. She holds an appointment in the
NICU Nurses
Department of Pediatrics, Faculty of Medicine, and the Faculty of
• Tuition Reimbursement • Nursing Congress
Nursing at the University of Manitoba. She maintains an active prac-
tice in the NICU at St. Boniface General Hospital and is the editor-in- • Clinical Ladder • Certification
chief of Neonatal Network: The Journal of Neonatal Nursing. • Education Resource Fund Reimbursement
• Preceptor Program • Shared Governance Model
For further information, please contact:
Yasser N. Elsayed, MD, PhD
University of Manitoba Faculty of Medicine Ask us about our transition incentives!*
Winnipeg, MB R3E 0L8
Canada
E-mail: yelsayed@exchange.hsc.mb.ca

Wilmington, NC

To hear how NHRMC offers a broad range

of opportunities in a supportive environment,
watch our video at
nursingatnhrmc.com
EOE M/F/D/V *Restrictions apply

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