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- increased arterial oxygen tension (vasoconstrictor effect) and
dynamic effects of PDA. This knowledge forms the basis of decreased placental prostaglandins (vasodilator effect). The
understanding how to gauge the significance of the patent sensitivity of preterm infants to these agents is incomplete or
ductus arteriosus and ultimately, determining which infants impaired. In preterm infants, these shunts frequently remain
may benefit from treatment. open and complicate already compromised hemodynamics
and autoregulatory mechanisms.12,13 Systemic vascular resis-
tance increases after removal of the low resistance placental
PERINATAL HEMODYNAMICS OF PDA circulation, a change which is usually well tolerated in term
Role of Ductus Arteriosus in the Fetal Hemodynamics and late preterm infants. In very premature or very low birth
In utero, oxygenated blood returns from placenta to the weight (VLBW) infants, this change in systemic vascular
fetus via the umbilical vein where it is directed, in part, resistance can result in impaired cardiac output because it
through the ductus venosus to join the inferior vena cava increases the afterload of the myocardium. Unlike the intra-
(IVC). To supply the needs of the brain, this oxygen-rich uterine environment where cardiac output comes from both
blood is preferentially directed through the foramen ovale ventricles, systemic postnatal circulation relies on output from
into the left heart, which pumps this blood to the upper body the left ventricle alone. Systemic flow can be further compro-
(brain) through the left ventricle. The less oxygenated blood mised if the ductus arteriosus remains open, allowing shunt-
from the liver and superior vena cava (SVC) is directed into ing from left to the right, shifting more blood away from
the right heart. The output from the right ventricle is shunted systemic flow to recirculate within the pulmonary circulation.
across the ductus arteriosus from the pulmonary artery to Systemic compromise can be more complex in the presence
the descending aorta, bypassing the lungs. Because of the of poor autoregulation of cerebral blood flow during the first
high pulmonary vascular resistance, ,20 percent of the fetal 12–36 hours after birth. Autoregulation gradually improves
cardiac output enters the fetal lungs.10 The combined cardiac over the first three days of life.12,13 Figure 2 summarizes the
output of the fetal heart is around 450 ml/kg/minute with hemodynamic effects of PDA in early postnatal circulation.
increasing right ventricular dominance through the second For a long time, it was thought that the brain was assigned
and third trimester. In utero, the shunt across the ductus as a vital organ with a highly protective autoregulatory mech-
arteriosus is right to left because of high pulmonary pres- anism. Current animal research work has shown that, in fact,
sure in the fetal lung.11,12 Figure 1 demonstrates antenatal in addition to the heart and adrenal gland, only the hindbrain
hemodynamics of PDA. is protected.14 This makes the forebrain vulnerable to postna-
tal white matter damage. Improvement of cerebral autoreg-
PDA and Transitional Circulation in Preterm Infants ulation, which occurs around 48–72 hours after birth, and
Postnatal cardiovascular adaptation is a complex process reperfusion of the brain parenchyma with increased cerebral
moving from parallel fetal circuits of circulation to an inte- blood flow may cause bleeding in the fragile choroid plexus
grated postnatal pulmonary and systemic circulatory pathway. leading to intraventricular hemorrhage (IVH).13 Figure 3
Once the lung starts to function for gas exchange and shows the effect of PDA on the development of IVH.
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 FACTORS AFFECTING HEMODYNAMIC
and late preterm infants.12 Closure of the PDA results from SIGNIFICANCE OF PDA
Determining the hemodynamic significance of a PDA is more
complex than equating the larger the size of the ductus with
FIGURE 1 ■ Role of the ductus in fetal circulation. clinical compromise. Many factors affect the volume of blood
moving through the ductus,6 including postnatal age and under-
High pulmonary vascular resistance Low systemic vascular resistance
lying medical conditions. Other factors include the following:
• Size and shape of the PDA: This is the most important
Ductus is shunting right
factor. A larger tube typically allows increased blood flow.
(pulmonary) to left (systemic) 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
High biventricular cardiac output
almost solely directed to systemic
through it.15
and only 10% to pulmonary circulation • Vascular resistance: Vascular resistance on either side of the
ductus (systemic or pulmonary) is the second most impor-
High fetal cardiac output is
tant factor and is the only factor that determines the direc-
important to compensate for low tion of the blood flow.16 Vascular resistance is the most
(antenatal) oxygen saturation 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 NATURAL HISTORY OF VASCULAR
responsive to various chemical and biological mediators RESISTANCE CHANGES IN
under both stable and disease conditions. Oxygen and oxi- PRETERM INFANTS
dative stresses, cytokines, and circulating prostaglandins Pulmonary artery pressure drops after birth because
are examples of theses mediators.17 of inflation of the lung and an increase in arterial oxygen
• The viscosity of the blood: Less viscous blood, for example, in tension. In the presence of a PDA, the decline in pulmonary
infants with anemia, results in a greater left-to-right shunt, artery pressure and the associated increase in systemic vas-
whereas less shunting occurs with polycythemia. 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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 pulmonary circulation will continue to increase, reaching
Factors that Alter Pulmonary as much as double or triple the systemic circulation instead
Vascular Resistance of maintaining the normal ratio of pulmonary-to-systemic
Factors which decrease pulmonary vascular resistance blood flow in the newborn of 0.8:1.2.22,23
• Hyperoxia
• Hyperventilation Effects of Overcirculation on the Lungs
• Alkalosis The balance between the volume of pulmonary circu-
• Pulmonary vasodilators (such as inhaled nitric oxide, lation and alveolar ventilation is normally maintained in
milrinone, prostacyclin, and sildenafil) equity to ensure a physiologic matching of gas exchange and
pulmonary circulation. In other words, each functioning
Factors which increase systemic vascular resistance alveolus should be ventilated and surrounded by a perfused
• Use of vasopressor medications such as norepinephrine capillary. This state of balance is expressed as a ventilation–
or vasopressin may increase systemic vascular resistance perfusion (V/Q) match. Pulmonary overcirculation with
and increase the magnitude of left-to-right shunt. On resulting edema can reduce the alveolar surface area for gas
the other hand, use of systemic vasodilators such as exchange, resulting in V/Q mismatch.10 This V/Q mis-
high doses of dobutamine or magnesium sulfate may match will be demonstrated by variable degrees of hypox-
lower systemic resistance and decrease the magnitude emia and hypoventilation and increasing need for respiratory
of left-to-right shunt; however this can further support.8,24 In these infants, the chest x-ray shows cardio-
compromise systemic blood flow. 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).
flow across the ductus. When right-sided heart pressures are Higher pulmonary vascular resistance is a protective
higher, the flow across the ductus moves from right-to-left mechanism which reduces the pressure on fragile alveolar
(pulmonary to systemic). Factors that alter pulmonary vas- capillary membranes, thereby reducing the risk of pulmo-
cular resistance are outlined in the sidebar. Because the left nary hemorrhage. Pulmonary overcirculation may lead to
ventricle begins to generate higher pressures, there is a shift acute pulmonary hemorrhage with the greatest period of risk
in blood flow resulting in a left-to-right shunt that may com- being the first seven days after birth in preterm infants born
promise the systemic blood flow.18 Moreover, because of sub- at ,29 weeks’ gestational age.25
optimal autoregulation in the first 12–24 hours after birth, Failure of ductal closure may lead to prolonged ventila-
changes in blood flow across the ductus may aggravate the tion and longer exposure to oxygen therapy. These, in turn,
transient pressure-passive blood flow to the brain.16
If the PDA remains open beyond first 72 hours of life,
FIGURE 4  hest x-ray of infant born at 24 weeks, postnatal age
C
increased blood flow from the systemic to the pulmonary cir- ■
6 weeks, shows cardiomegaly and congested lung
culation may result in pulmonary edema. A significant amount fields because of large patent ductus arteriosus.
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 This x-ray was taken one day before patent ductus arteriosus (PDA)
blood flow.21 If the PDA persists or medical closure fails, the ligation.

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 can cause continued lung injury with impaired alveolization. compensatory and autoregulatory mechanisms further induce
Prolonged ventilation increases the risk for prolonged hos- renal damage and cause end organ failure.39
pitalization, ventilator-associated pneumonia, and other
infections. 26 Long-term exposure of the lungs to over- HSPDA and Cardiac Performance
circulation may predispose to the infant to chronic lung Volume overload of the left heart with HSPDA causes
changes and bronchopulmonary dysplasia (BPD). Recent diastolic dysfunction which can be detected by Doppler
evidence suggests that early evaluation of the PDA may evaluation of mitral, pulmonary veins, and tissue Doppler
assist in predicting the risk of BPD. 27 In a large multicenter indices. 27 The systolic function may be normal or hyper-
study, hemodynamically signif icant patent ductus arte- dynamic with increased fractional shortening and high
riosus (HSPDA) in preterm infants was associated with left cardiac output.40 In the presence of high left cardiac
increased risk of chronic lung disease, regardless of the output, more blood is diverted across the PDA from the
time of closure, with an odds ratio of 1.9. 28 However, no systemic circulation to the pulmonary circulation resulting
treatment modality for PDA has been shown to prevent in pulmonary edema and further compromise to the sys-
chronic lung disease. 29–31 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
SYSTEMIC CONSEQUENCES OF and has been attributed to factors such as a sudden increase
LEFT-TO-RIGHT PDA SHUNT in afterload and decrease in preload, exposure to anesthesia,
Diverting or stealing blood f low from the systemic to and adrenal dysfunction.44,45
pulmonary circulation may lead to decreased blood flow to
body organs such as the gut and the kidneys. Compromised HSPDA and Neurodevelopment
systemic perfusion is greater during the diastolic phase of In the longer term, neurodevelopmental delay is the most
circulation, and the effect of diminished blood flow on the challenging outcome that needs to be addressed. Long-term
organs depends on the organs’ intrinsic capacities to com- exposure of white matter to compromised blood flow from
pensate for decreased blood flow through autoregulation. a PDA may lead to injury which affects neuronal develop-
Because autoregulation improves after birth, the effects of ment.13,18,46 In spite of this plausible relationship between
a PDA on the brain and on myocardial perfusion may be PDA and neurodevelopment, there are no randomized, con-
lessened.32 Systemic signs of PDA may include hypotension, trolled trials showing that either prophylaxis or treatment
especially affecting the diastolic pressure; metabolic acidosis; improves long-term outcomes.35,47,48
and oliguria.9

HSPDA and Necrotizing Enterocolitis RISKS OF TREATING A PDA

Research has shown an increased risk of necrotizing Aggressive treatment of HSPDA has been associated with
enterocolitis (NEC) in the presence of a PDA. In fact, a PDA increased morbidity and mortality. In an analysis of PDA
is an independent risk factor for NEC with an odds ratio of management done over a five-year period by the Canadian
1.8.33 Again, prophylactic or rescue treatment of the PDA Neonatal Network, PDA ligation was associated with an
has not been shown to decrease the incidence of NEC.34,35 increased risk of NEC (Stages 2 and 3), ROP (Stages 3, 4,
A case series showed the development of NEC after blood and 5), and BPD when compared to medical treatment or
transfusion in cases with significant PDA; we speculate that conservative management.47 Any treatment strategy must
exposure of the gut to reperfusion–reoxygenation injury may balance the risk of shunt on hemodynamics and the impact
explain transfusion-associated NEC in preterm infants with of treatment.
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 THE EFFECT OF A PDA ON
injury of the gut, leading to NEC.33 NEONATAL OUTCOME
The relationship between PDA and outcomes cannot be
HSPDA and Renal Impairment viewed as a direct causal relationship. There are two main
Increased left-to-right blood flow through a PDA during pathophysiologic pathways that can cause cellular compro-
diastole may cause renal failure secondary to hypoperfusion. mise and lead to long-term unfavorable outcomes in neo-
Signs of renal failure include increased creatinine, hypona- nates. These pathways include compromised blood f low
tremia, and oliguria. Activation of the renin–angiotensin– and oxygen homeostasis which initiates an inf lammatory
aldosterone system may aggravate both renal and heart failure.37 process and any respiratory condition that disturbs oxygen
Volume overload of the left heart can increase the serum level homeostasis. There is an overlap between these two pathways
of B-type natriuretic peptide (BNP). B-type natriuretic peptide (Figure 5).49–52 All preterm infants are exposed to variable
has a compensatory vasodilator and diuretic effect.38 Failure of degrees and multiple causes of inflammation and disturbed

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 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- 3. Chock VY, Punn R, Oza A, et al. Predictors of bronchopulmonary
tions, and NEC.9 Therefore, it becomes difficult to directly dysplasia or death in premature infants with a patent ductus arteriosus.
Pediatr Res. 2014;75(4):570-575. http://dx.doi.org/10.1038/pr
determine the contribution of a HSPDA to long-term .2013.253
outcomes. 4. Sehgal A, Paul E, Menahem S. Functional echocardiography in staging
for ductal disease severity: role in predicting outcomes. Eur J Pediatr.
2013;172(2):179-184. http://dx.doi.org/10.1007/s00431-012-1851-0
SUMMARY 5. Heuchan AM, Hunter L, Young D. Outcomes following the surgical
HSPDA has a significant effect on both pulmonary and ligation of the patent ductus arteriosus in premature infants in Scotland.
systemic circulations, which, in turn, impacts both short- and Arch Dis Child Fetal Neonatal Ed. 2012;97(1):F39-F44. http://dx.doi
.org/10.1136/adc.2010.206052
long-term outcomes. In utero, the ductus arteriosus plays an
important role in the distribution of cardiac output. After 6. McNamara PJ, Jain A. Patent ductus arteriosus treatment in preterm
infants-time to consider shunt volume? J Perinatol. 2013;33(3):248-249.
birth, ongoing ductal patency impacts blood flow to several http://dx.doi.org/10.1038/jp.2012.104
organs including the brain, heart, lungs, and kidneys. Altered 7. de Waal K, Kluckow M. Functional echocardiography; from physiology
blood flow to these organs has the potential to impact short- to treatment. Early Hum Dev. 2010;86(3):149-154. http://dx.doi
and long-term clinical outcomes. Through a better under- .org/10.1016/j.earlhumdev.2010.01.030
standing of the impact of the PDA on hemodynamics in 8. Elsayed Y, Fraser D. Integrated evaluation of neonatal hemodynamics,
preterm infants, it is possible to develop a systematic approach part 2: systematic bedside assessment. Neonatal Netw. 2016;35(4):192-203.
to assessing the impact of these changes on individual organs 9. Elsayed Y, Fraser D. Integrated evaluation of neonatal hemodynamics
and to better target those neonates for whom treatment is program optimizing organ perfusion and performance in critically ill
neonates, part 1: understanding physiology of neonatal hemodynamics.
warranted.
Neonatal Netw. 2016;35(3):143-150.
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: [email protected]

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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