Patent Ductus Arteriosus in the Preterm Infant

Key Points

Clinical signs of a symptomatic patent ductus arteriosus (PDA) usually appear later than echocardiographic signs and are related to the degree of left-to-right ductal shunting.
Factors known to play a prominent role in regulation of ductal patency involve those that promote constriction (oxygen, endothelin, calcium channels, catecholamines, and Rho kinase) and those that oppose it (intraluminal pressure, prostaglandins, nitric oxide, carbon monoxide, potassium channels, and cyclic adenosine monophosphate and guanosine monophosphate).
Closure of the ductus arteriosus occurs in two phases: (1) “functional” closure of the lumen by smooth muscle constriction, within hours after birth and (2) “anatomic” occlusion of the lumen over the next several days, due to neointimal thickening and loss of smooth muscle cells from the inner muscle media.
The most important mechanism that prevents the preterm ductus from constricting after birth is its increased sensitivity to the vasodilating effects of prostaglandin E2. Inhibitors of prostaglandin production (e.g., indomethacin, ibuprofen, acetaminophen) are usually effective in promoting ductus closure in preterm infants.
Early surgical ligation, while eliminating the detrimental effects of a PDA on lung development, may create its own set of problems for the preterm infant that counteract those benefits (e.g., postligation hypotension, bronchopulmonary dysplasia, vocal cord paralysis, neurodevelopmental abnormalities).
While there may be general consensus on the efficacy of cyclooxygenase inhibitors for treatment of a PDA, questions about proper dosage, treatment duration, optimal timing, and treatment criteria remain controversial.
Although a moderate-to-large PDA increases pulmonary blood flow and edema and decreases systemic blood pressure, it is not clear which is preferable: (1) to close the PDA (surgically or pharmacologically) or (2) to deal with the pulmonary edema and hypotension through other means, while awaiting spontaneous ductal closure.
Further investigation is needed to determine which preterm infants are most likely to benefit from ductal closure and which might be best left untreated.

Introduction

The ductus arteriosus represents a persistence of the terminal portion of the sixth branchial arch. During fetal life, the ductus arteriosus serves to divert blood away from the fluid-filled lungs toward the descending aorta and placenta. After birth, constriction of the ductus arteriosus and obliteration of its lumen separate the pulmonary and systemic circulations. In full-term infants, obliteration of the ductus arteriosus takes place through a process of vasoconstriction and anatomic remodeling. In the preterm, the ductus arteriosus frequently fails to close. The clinical consequences of a patent ductus arteriosus (PDA) are related to the degree of left-to-right PDA shunt with its associated change in blood flow to the lungs, kidneys, and intestine.

Diagnosis

Phase contrast magnetic resonance imaging offers the most accurate measurements of ductal shunt volume, and the effects of a PDA on left ventricular and systemic blood flow volumes. Unfortunately, these measurements are difficult to obtain in extremely immature, sick preterm infants. Two-dimensional echocardiography and color Doppler flow mapping is the current standard for assessing the presence, magnitude, and direction of PDA shunting. Ductus diameter ≥1.5 mm (or >50% of the diameter of the left pulmonary artery), left atrial-to–aortic root (LA/Ao) ratio ≥1.5, reversal of forward blood flow in the descending aorta during diastole, and end diastolic flow velocity in the left pulmonary artery ≥0.20 m/s are signs consistent with a moderate-to-large PDA shunt. Unfortunately, the inter-observer repeatability of all echocardiographic parameters is relatively poor.

Clinical signs of a PDA (systolic murmur, hyperdynamic precordial impulse, full pulses, widened pulse pressure, and/or worsening respiratory status) usually appear later than echocardiographic signs and are less sensitive in determining the degree of left-to-right shunt. Certain signs such as continuous murmur or hyperactive left ventricular impulse are relatively specific for a PDA but lack sensitivity; conversely, worsening respiratory status, while a sensitive indicator, is relatively nonspecific for a PDA. Tachycardia is not a useful or reliable indicator of a PDA in preterm infants. Infants with large left-to-right shunts may have evidence of cardiomegaly and increased pulmonary arterial markings on their chest x-rays; however, in general, the chest x-ray and electrocardiogram are not useful in diagnosing a PDA. Although elevated plasma concentrations of brain natriuretic peptide (BNP) and N-terminal pro-BNP (NTpBNP) have been found to correlate with the presence of a moderate sized left-to-right PDA shunt, changes in BNP and N-terminal pro-BNP concentrations have poor sensitivity and specificity in predicting increases or decreases in PDA shunt magnitude and cannot be used to replace echocardiography in the management of PDA shunts. Although there has been little consensus in the past about what constitutes a clinically important PDA, recent studies have shown that moderate and large PDA shunts are associated with significant neonatal morbidities, whereas small PDA shunts have similar outcomes as no PDA shunts. Although PDA shunt magnitude plays a significant role in creating its hemodynamic significance, equally important are the duration of shunt exposure, infant’s gestational age, ventricular diastolic function, and need for invasive respiratory support.

Incidence ( Table 48.1 )

Functional closure of the ductus occurs in almost 50% of full-term infants by 24 hours, in 90% by 48 hours, and in all by 72 hours. The rate of ductus closure is delayed in preterm infants; however, essentially all preterm infants who are ≥30 weeks’ gestation (including those with respiratory distress syndrome) will close their ductus by the fourth day after birth. Infants born at less than 30 weeks’ gestation have a 65% incidence of persistent ductus patency beyond day 4. Even among the most immature infants (≤27 weeks’ gestation), spontaneous closure can occur during the neonatal period. However, when it does occur, it usually occurs late during the NICU hospitalization (average age = 61 ± 37 days). Among preterm infants discharged from the hospital with a persistent PDA, 86% will achieve PDA closure by 1 year of age. The remainder will require continued observation or device closure.

Table 48.1

Incidence of Patent Ductus Arteriosus Among Infants Less Than 30 Weeks’ Gestation

Data from references. .

Presence of PDA (Any Size) (%)
Gestation (wk)	Day 4	Day 7	Day 20	Day 40	Day 60	Day 80
28–29	55	33	20	10	8
26–27	84	68	48	38	27	27
24–25	96	87	75	72	56	38

Presence of Hemodynamically Significant PDA (%) *
Gestation (wk)	Day 4	Day 7	Day 20	Day 40	Day 60	Day 80
27–28		21	13	5	1	0
25–26		64	50	22	3	0
23–24		93	88	58	33	14

* Ductus diameter ≥2 mm on echocardiography plus need for ventilator support

Factors like surfactant administration, infection, being small for gestational age at 26 to 29 weeks, and excessive fluid administration increase the likelihood of developing a symptomatic PDA. On the other hand, being small for gestational age at 23 to 24 weeks, nonwhite, or having received antenatal glucocorticoids reduce risk of PDA.

Regulation of Ductus Patency—Vasoconstriction and Vasorelaxation

In Utero Regulation

Ductus arteriosus patency is determined by the balance between dilating and constricting forces. Smooth muscle tone in the ductus arteriosus is determined by the phosphorylation and dephosphorylation of myosin light chains. The fetal ductus has a high level of intrinsic tone due to elevated levels of intracellular calcium (Ca ²⁺ ) which activate myosin light chain kinase, producing myosin light chain phosphorylation and smooth muscle constriction. Extracellular Ca ²⁺ enters the smooth muscle cytosol primarily through voltage-operated Ca ²⁺ channels (Ca _L and T-type channels) and transient receptor potential (TRP) channels in the plasma membrane. Calcium is also released from intracellular stores in the sarcoplasmic and endoplasmic reticulum (SR and ER) through ryanodine receptors and inositol 1,4,5-trisphosphate receptors (IP3Rs).

The contractile proteins in the fetal ductus (smooth muscle myosin, calponin, and caldesmon) are more differentiated and more sensitive to the contractile effects of Ca ²⁺ than they are the aorta and the pulmonary artery. Increased Rho kinase activity in the ductus increases smooth muscle sensitivity to Ca ²⁺ by inhibiting myosin light chain dephosphorylation. Endothelin-1 plays a role in the elevated basal tone of the fetal ductus arteriosus by inducing IP3 and releasing Ca ²⁺ from the sarcoplasmic reticulum. Recently, a role for serotonin in promoting fetal ductus tone has been suggested since selective serotonin reuptake inhibitors constrict the ductus in utero.

The factors that oppose ductus arteriosus constriction in utero are better understood. The elevated vascular pressure within the ductus lumen (due to the high resistance in the constricted pulmonary vascular bed) plays an important role in opposing ductus constriction.

K ⁺ channels buffer ductus tone by regulating the rate of extracellular Ca ²⁺ entry into the smooth muscle cells. When K ⁺ channels are open, K ⁺ exits the cell turning the membrane potential more negative (i.e., hyperpolarizing the cell). Hyperpolarization inhibits extracellular Ca ²⁺ influx through voltage-gated L-type Ca ²⁺ (CaL) channels. Several K ⁺ channels [voltage-gated (Kv), Ca ²⁺ -activated (K _Ca ), and ATP-dependent (K _ATP )] K ⁺ channels are present in fetal ductus smooth muscle cells. Their relative contribution to resting membrane potential depends on the animal species and the stage of development.

The fetal ductus also produces vasodilators that help to maintain ductus patency. Prostaglandins (PGs) are the dominant vasodilators that oppose ductus constriction in the later part of gestation. Inhibitors of PG synthesis constrict the fetal ductus. PGE ₂ is the most potent PG produced by the ductus and appears to be the most important prostanoid to regulate ductus patency. The ductus is extraordinarily sensitive to the vasodilating effects of PGE ₂ . In the ductus, all three of the PGE receptors (EP2, EP3, and EP4) participate in vasodilation by activating adenylate cyclase and increasing ductus smooth muscle cyclic adenosine monophosphate (AMP) (which inhibits myosin light chain kinase and myosin light chain phosphorylation, thereby inhibiting the sensitivity of the contractile proteins to calcium). Low levels of phosphodiesterase (the enzyme that degrades cyclic AMP) in the fetal ductus account for the vessel’s increased sensitivity to PGE2. PGE _{2, acting through} EP3 receptors (in lamb) and EP4 receptors (in rabbit), also activates the K _ATP and Kv channels, respectively, increasing outward K ⁺ current, hyperpolarizing the cell, and further inhibiting Ca ²⁺ influx.

Both isoforms of the enzyme responsible for synthesizing PGs (cyclooxygenase [COX]-1 and COX-2) are expressed in the fetal ductus. In the fetal mouse, COX-2 appears to be the COX isoform responsible PGE2 production, whereas in the fetal sheep, both COX-1 and COX-2 play a role. High circulating PGE ₂ , originating from the placenta, also regulates fetal ductus behavior, due to low in utero pulmonary clearance.

Nitric oxide, formed mainly by eNOS, is made by the fetal ductus arteriosus and appears to play an important role in maintaining ductus patency in rodent fetuses early in gestation. NO activates soluble guanylyl cyclase increasing ductus smooth muscle cyclic GMP (cGMP) and cGMP-dependent protein kinase (PKG). PKG decreases intracellular Ca ²⁺ by inhibiting Ca ²⁺ influx, stimulating its removal, and by inhibiting the Rho-kinase pathway. PGE ₂ and NO are coupled for reciprocal compensation since cyclooxygenase inhibition upregulates NO. The importance of NO in maintaining in utero patency in larger species has not been conclusively demonstrated (see below).

Carbon monoxide (CO) relaxes the ductus arteriosus. Under physiologic conditions the amount of CO made by the ductus does not seem to affect ductus tone; however, in circumstances where its synthesis is upregulated, for example, endotoxemia, CO may exert a relaxing influence on the ductus. Hydrogen sulfide (made by ductus endothelial and smooth muscle cells) also has been identified as another endogenous factor that inhibits fetal ductus tone by opening K _ATP channels.

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