Patent Ductus Arteriosus (PDA)

Patent ductus arteriosus (PDA), in which there is a persistent communication between the descending thoracic aorta and the pulmonary artery that results from failure of normal physiologic closure of the fetal ductus (see image below), is one of the more common congenital heart defects.

Schematic diagram of a left-to-right shunt of blood flow from the descending aorta via the patent ductus arteriosus (PDA) to the main pulmonary artery.

The patient presentation of patent ductus arteriosus (PDA) varies widely. Although frequently diagnosed in infants, the discovery of this condition may be delayed until childhood or even adulthood. In isolated patent ductus arteriosus (PDA), signs and symptoms are consistent with left-to-right shunting. The shunt volume is determined by the size of the open communication and the pulmonary vascular resistance (PVR).

Patent ductus arteriosus (PDA) may also exist with other cardiac anomalies, which must be considered at the time of diagnosis. In many cases, the diagnosis and treatment of a patent ductus arteriosus (PDA) is critical for survival in neonates with severe obstructive lesions to either the right or left side of the heart.

Historical information

Galen initially described the ductus arteriosus in the early first century. Harvey undertook further physiologic study in fetal circulation. However, it was not until 1888 that Munro conducted the dissection and ligation of the ductus arteriosus in an infant cadaver, and it would be another 50 years before Robert E. Gross successfully ligated a patent ductus arteriosus (PDA) in a 7-year-old child.[1] This was a landmark event in the history of surgery and heralded the true beginning of the field of congenital heart surgery. Catheter-based closure of the structure was first performed in 1971.

See also Patent Ductus Arteriosus Surgery and Eisenmenger Syndrome.

During fetal life, the ductus arteriosus is a normal structure that allows most of the blood leaving the right ventricle to bypass the pulmonary circulation and pass into the descending aorta. Typically, only about 10% of the right ventricular output passes through the pulmonary vascular bed.

The ductus arteriosus is a remnant of the distal sixth aortic arch and connects the pulmonary artery at the junction of the main pulmonary artery and the origin of the left pulmonary artery to the proximal descending aorta just after the origin of the left subclavian artery. It passes from the anterior aspect of the pulmonary artery to the posterior aspect of the aorta. Typically, the ductus has a conical shape with a large aortic end tapering into the small pulmonary connection. The ductus may take many shapes and forms, from short and tubular to long and tortuous.

An anatomic marker of the ductus is the recurrent laryngeal nerve, which nerve typically arises from the vagus nerve just anterior and caudal to the ductus and loops posteriorly around the ductus to ascend behind the aorta en route to the larynx. It is the most commonly injured anatomic structure in ductal ligation. Other less commonly injured structures include the phrenic nerve and the thoracic duct.

Most typically, the patent ductus arteriosus (PDA) is a left aortic remnant; however, it can be right-sided or on both the left side and right side. Although a left ductus arteriosus is a normal structure during normal fetal development, the presence of a right ductus arteriosus is usually associated with other congenital abnormalities of the cardiovascular system, most typically involving the aortic arch or conotruncal development.

The Krichenko classification of PDA is based on angiography and includes type A (conical), type B (window), type C (tubular), type D (complex), and type E (elongated) PDA.

In the presence of complex congenital heart defects, the usual anatomy of the ductus may not be present. Anatomic abnormalities can vary widely and are common in conjunction with complex aortic arch anomalies. Structures that have been mistaken for the patent ductus arteriosus (PDA) in surgical procedures include the aorta, the pulmonary artery, and the carotid artery.

The ductus arteriosus is normally patent during fetal life; it is an important structure in fetal development as it contributes to the flow of blood to the rest of the fetal organs and structure. From the 6th week of fetal life onwards, the ductus is responsible for most of the right ventricular outflow, and it contributes to 60% of the total cardiac output throughout the fetal life. Only about 5-10% of its outflow passes through the lungs.

This patency is promoted by continual production of prostaglandin E2 (PGE2) by the ductus. Closure of the ductus before birth may lead to right heart failure. Prostaglandin antagonism, such as maternal use of nonsteroidal anti-inflammatory medications (NSAIDs), can cause fetal closure of the ductus arteriosus.

Thus, a patent ductus arteriosus (PDA) produces a left-to-right shunt. In other words, it allows blood to go from the systemic circulation to the pulmonary circulation. Therefore, pulmonary blood flow is excessive (see the image below). Pulmonary engorgement results with decreased pulmonary compliance. The reaction of the pulmonary vasculature to the increased blood flow is unpredictable.

Schematic diagram of a left-to-right shunt of blood flow from the descending aorta via the patent ductus arteriosus (PDA) to the main pulmonary artery.

The magnitude of the excess pulmonary blood flow depends on relatively few factors. The larger the internal diameter of the most narrow portion of the ductus arteriosus, the larger the left-to-right shunt. If the ductus arteriosus is restrictive, then the length of the narrowed area also affects the magnitude of the shunt. A longer ductus is associated with a smaller shunt. Finally, the magnitude of the left-to-right shunt is partially controlled by the relationship of the pulmonary vascular resistance (PVR) to the systemic vascular resistance (SVR).

If the SVR is high and/or the PVR is low, the flow through the ductus arteriosus is potentially large. Beginning at the ductus arteriosus, the course of blood flow (through systole and diastole) in a typical patent ductus arteriosus (PDA) with pulmonary overcirculation is as follows: patent ductus arteriosus (PDA), pulmonary arteries, pulmonary capillaries, pulmonary veins, left atrium, left ventricle, aorta, patent ductus arteriosus (PDA). Therefore, a large left-to-right shunt through a patent ductus arteriosus (PDA) results in left atrial and left ventricular enlargement. The pulmonary veins and the ascending aorta can also be dilated with a sufficiently large patent ductus arteriosus (PDA). In addition, if little or no restriction is present at the level of the patent ductus arteriosus (PDA), pulmonary hypertension results.

Functional and anatomic closure

In the fetus, the oxygen tension is relatively low, because the pulmonary system is nonfunctional. Coupled with high levels of circulating prostaglandins, this acts to keep the ductus open. The high levels of prostaglandins result from the little amount of pulmonary circulation and the high levels of production in the placenta.

At birth, the placenta is removed, eliminating a major source of prostaglandin production, and the lungs expand, activating the organ in which most prostaglandins are metabolized. In addition, with the onset of normal respiration, oxygen tension in the blood markedly increases. Pulmonary vascular resistance decreases with this activity.

Normally, functional closure of the ductus arteriosus occurs by about 15 hours of life in healthy infants born at term. This occurs by abrupt contraction of the muscular wall of the ductus arteriosus, which is associated with increases in the partial pressure of oxygen (PO2) coincident with the first breath. A preferential shift of blood flow occurs; the blood moves away from the ductus and directly from the right ventricle into the lungs. Until functional closure is complete and PVR is lower than SVR, some residual left-to-right flow occurs from the aorta through the ductus and into the pulmonary arteries.

This was first demonstrated by multiple experiments in the 1940s and has been subsequently confirmed. Although the neonatal ductus appears to be highly sensitive to changes in arterial oxygen tension, the actual reasons for closure or persistent patency are complex and involve manipulation by the autonomic nervous system, chemical mediators, and the ductal musculature.

A balance of factors that cause relaxation and contraction determine the vascular tone of the ductus. Major factors causing relaxation are the high prostaglandin levels, hypoxemia, and nitric oxide production in the ductus. Factors resulting in contraction include decreased prostaglandin levels, increased PO2, increased endothelin-1, norepinephrine, acetylcholine, bradykinin, and decreased PGE receptors. Increased prostaglandin sensitivity, in conjunction with pulmonary immaturity leading to hypoxia, contributes to the increased frequency of patent ductus arteriosus (PDA) in premature neonates.

Although functional closure usually occurs in the first few hours of life, true anatomic closure, in which the ductus loses the ability to reopen, may take several weeks. A second stage of closure related to fibrous proliferation of the intima is complete in 2-3 weeks.

Cassels et al defined true persistence of the ductus arteriosus as a patent ductus arteriosus (PDA) present in infants older than 3 months.[2] Thus, patency after 3 months is considered abnormal, and treatment should be considered at this juncture, although urgency is seldom necessary. Some canine breeds, such as certain strains of poodle, have a large prevalence of patent ductus arteriosus (PDA).

Spontaneous closure after 5 months is rare in the full-term infant. Left untreated, patients with a large patent ductus arteriosus (PDA) are at risk to develop Eisenmenger Syndrome, in which the PVR can exceed SVR, and the usual left-to-right shunting reverses to a right-to-left direction. At this stage, the PVR is irreversible, closure of the patent ductus arteriosus (PDA) is contraindicated, and lung transplantation may be the only hope for long-term survival.

Failure of ductus arteriosus to contract

Failure of ductus arteriosus contraction in preterm neonates has been suggested to be due to poor prostaglandin metabolism because of immature lungs. Furthermore, high reactivity to prostaglandin and reduced calcium sensitivity to oxygen in vascular smooth muscle cells contribute to contraction of the ductus. The absence of ductus arteriosus contraction in full-term neonates might be due to failed prostaglandin metabolism most likely caused by hypoxemia, asphyxia, or increased pulmonary blood flow, renal failure, and respiratory disorders.

Cyclooxygenase (COX)-2 (an isoform of COX-producing prostaglandins) induction and expression might also prevent ductal closure. The activation of G protein-coupled receptors EP4 by PGE2, the primary prostaglandin regulating ductal tone leads to ductal smooth muscle relaxation.

During late gestation, the decrease in prostaglandin levels results in constriction of the ductus arteriosus. Thus, the intimal cushions come into contact and occlude the ductus lumen.

Volume-pressure relationships

Further progression of disease is dependent on volume and pressure relationships, as follows:

• Volume = pressure/resistance

• High volume yields increasing pulmonary artery pressures, eventually producing endothelial and muscular changes in the vessel wall

• These changes may eventually lead to pulmonary vascular obstructive disease (PVOD), a condition of resistance to pulmonary blood flow that may be irreversible and will preclude definitive repair

Genetics

Familial cases of patent ductus arteriosus (PDA) have been recorded, but a genetic cause has not been determined. In infants born at term who have a persistent patent ductus arteriosus (PDA), the recurrence rate among siblings is 5%. Some early evidence suggests that as many as one third of cases are caused by a recessive trait labeled PDA1, located on chromosome 12, at least in some populations.

Chromosomal abnormalities

Several chromosomal abnormalities are associated with persistent patency of the ductus arteriosus. Implicated teratogens include congenital rubella infection in the first trimester of pregnancy, particularly through 4 weeks' gestation (associated with patent ductus arteriosus [PDA] and pulmonary artery branch stenosis), fetal alcohol syndrome, maternal amphetamine use, and maternal phenytoin use.

Prematurity

Prematurity or immaturity of the infant at the time of delivery contributes to the patency of the ductus. Several factors are involved, including immaturity of the smooth muscle within the structure or the inability of the immature lungs to clear the circulating prostaglandins that remain from gestation. These mechanisms are not fully understood. Conditions that contribute to low oxygen tension in the blood, such as immature lungs, coexisting congenital heart defects, and high altitude, are associated with persistent patency of the ductus.

Other

Other causes include low birth weight (LBW), prostaglandins, high altitude and low atmospheric oxygen tension, and hypoxia.

The estimated incidence of patent ductus arteriosus (PDA) in US children born at term is between 0.02% and 0.006% of live births. This incidence is increased in children who are born prematurely (20% in premature infants > 32 weeks' gestation up to 60% in those < 28 weeks' gestation), children with a history of perinatal asphyxia, and, possibly, children born at high altitude. In addition, up to 30% of low birth weight infants (< 2500 g) develop a patent ductus arteriosus (PDA). Siblings also have an increased incidence. Perinatal asphyxia usually only delays the closure of the ductus, and, over time, the ductus typically closes without specific therapy.

As an isolated lesion, patent ductus arteriosus (PDA) represents 5-10% of all congenital heart lesions. It occurs in approximately 0.008% of live premature births.

No data support a race predilection. However, there is a female preponderance (female-to-male ratio, 2:1) if the patent ductus arteriosus (PDA) is not associated with other risk factors. In patients in whom the patent ductus arteriosus (PDA) is associated with a specific teratogenic exposure, such as congenital rubella, the incidence is equal between the sexes.

Occasionally, an older child is referred with the late discovery of a typical ductus arteriosus murmur (eg, machinery or continuous murmur).

The prognosis is generally considered excellent in patients in whom the patent ductus arteriosus (PDA) is the only problem. In premature infants who have other sequelae of prematurity, these sequelae tend to dictate prognosis of patent ductus arteriosus (PDA).

Typically, following patent ductus arteriosus (PDA) closure, patients experience no further symptoms and have no further cardiac sequelae. Premature infants who had a significant patent ductus arteriosus (PDA) are more likely to develop bronchopulmonary dysplasia.

Spontaneous closure in those older than 3 months is rare. In those younger than 3 months, spontaneous closure in premature infants is 72-75%. In addition, 28% of children with patent ductus arteriosus (PDA) who were conservatively treated (with prophylactic ibuprofen) reported a 94% closure rate. This rate compared well with rates reported in literature following medical treatment (80-92%).

In the adult patient, the prognosis is more dependent on the condition of the pulmonary vasculature and the status of the myocardium if congestive cardiomyopathy was present before ductal closure. Patients with minimal or reactive pulmonary hypertension and limited myocardial changes may have a normal life expectancy.

Morbidity

Morbidity and mortality rates are directly related to the flow volume through the ductus arteriosus. A large patent ductus arteriosus (PDA) may cause congestive heart failure (CHF); if left untreated for a long period, pulmonary hypertension may develop. Occasionally, the ductus arteriosus patency can be intermittent.

Low birth weight premature infants

As many as 20% of neonates with respiratory distress syndrome have patent ductus arteriosus (PDA). In babies who are less than 1500 g at birth, many studies show the incidence of a patent ductus arteriosus (PDA) to exceed 30%. The increased patency in these groups is thought to be due to both hypoxia in babies with respiratory distress and immature ductal closure mechanisms in premature babies.

Premature babies, particularly low birth weight neonates, are more likely to have problems related to patent ductus arteriosus (PDA). Spontaneous closure of the patent ductus arteriosus (PDA ) in premature neonates is common, but respiratory distress and impaired systemic oxygen delivery (CHF) often drive the need for therapy to effect ductal closure in this group. Low birth weight neonates with a patent ductus arteriosus (PDA) are more likely to develop chronic lung disease.

Mortality

No firm statistics exist, but survival rates are decreased in patients with large shunts. The surgical mortality rate in premature infants ranges from 20% to 41%. With the availability of antibiotics to treat endocarditis and low-risk surgery and catheter techniques to obliterate the patent ductus arteriosus (PDA), the mortality rate appears to be quite low except in the extremely premature infant.

It is estimated that left untreated, the mortality rate for patent ductus arteriosus (PDA) is 20% by age 20 years, 42% by age 45 years, and 60% mortality rate by age 60 years. An estimated 0.6% per year undergoes spontaneous closure.

As discussed in Pathophysiology, the ductus arteriosus is always patent in the fetus if the cardiovascular system is otherwise normal. Normally, the ductus arteriosus closes functionally in the first 10-18 hours of life. Prematurity, perinatal distress, and hypoxia delay closure of the ductus arteriosus; however, most children who are found to have a ductus arteriosus have no history of precedent risk factors.

Depending on the size of the patent ductus arteriosus (PDA), the gestational age of the neonate, and the pulmonary vascular resistance (PVR), a premature neonate may develop life-threatening pulmonary overcirculation in the first few days of life. Conversely, an adult with a small patent ductus arteriosus (PDA) may present with a newly discovered murmur well after adolescence.

Symptoms

Patients can present at any age. The typical child with a patent ductus arteriosus (PDA) is asymptomatic. At times, the patient may report decreased exercise tolerance or pulmonary congestion in conjunction with a murmur.

Three-week to 6-week-old infants can present with tachypnea, diaphoresis, inability or difficulty with feeding, and weight loss or no weight gain.

A ductus arteriosus with a moderate-to-large left-to-right shunt may be associated with a hoarse cry, cough, lower respiratory tract infections, atelectasis, or pneumonia. With large defects, the patient may have a history of feeding difficulties and poor growth during infancy, described as failure to thrive (FTT). However, frank symptoms of congestive heart failure (CHF) are rare.

Adults whose patent ductus arteriosus (PDA) has gone undiagnosed may present with signs and symptoms of heart failure, atrial arrhythmia, or even differential cyanosis limited to the lower extremities, indicating shunting of unoxygenated blood from the pulmonary to systemic circulation.

A patent ductus arteriosus (PDA) is variable in its presentation. It may vary in size from small to large and may not be picked up based on physical examination at birth.

Patients usually appear well and have normal respirations and heart rates. A widened pulse pressure may be noted when the blood pressure is obtained. Suprasternal or carotid pulsations may be prominent.

As many as one third of children with patent ductus arteriosus (PDA) is small for their age. In the presence of significant pulmonary overcirculation, tachypnea, tachycardia, and a widened pulse pressure may be found.

Cardiac assessment

In neonates, a heart murmur is discovered within the first few days or weeks of life. The murmur is usually recognized as systolic rather than continuous in the first weeks of life and can mimic a benign systolic murmur.

Findings upon cardiac examination include the following:

• If the left-to-right shunt is large, precordial activity is increased, with the magnitude of increased activity related to the magnitude of left-to-right shunt

• The apical impulse is laterally displaced; a thrill may be present in the suprasternal notch or in the left infraclavicular region

• The first heart sound (S1) is typically normal, and the second heart sound (S2) is often obscured by the murmur; phonocardiographic data from the past suggested the occurrence of paradoxical splitting of S2 related to premature closure of the pulmonary valve and a prolonged ejection period across the aortic valve

• The murmur may be only a systolic ejection murmur, or it may be a crescendo/decrescendo systolic murmur that extends into diastole

• Occasionally, auscultation of the patent ductus arteriosus (PDA) reveals numerous clicks or noises resembling shaking dice or a bag of rocks

In 1898, Gibson described the classic murmur. Subsequently, the hallmark physical finding of patent ductus arteriosus (PDA) has been referred to as a machinery murmur, which is continuous. The murmur may be accentuated in systole. Typically, the murmur is loudest at the left upper chest. If the pulmonary-to-systemic blood ratio approaches or exceeds 2:1, an apical flow rumble, caused by high flow into the left ventricle, is frequently present. Also, because flow through the left ventricle into the aorta is increased, an aortic ejection murmur may be present. If the patent ductus arteriosus (PDA) is small, the amplitude of the murmur may increase with inspiration as pulmonary impedance drops.

The peripheral pulses are often referred to as bounding. This is related to the high left ventricular stroke volume, which may cause systolic hypertension. The phenomenon of bounding pulses also is caused by the low diastolic pressure in the systemic circulation as blood runs off from the aorta into the pulmonary circulation.

Low birth weight premature infant

In the low birth weight premature infant, diagnosing a patent ductus arteriosus (PDA) on auscultation may be difficult. Babies that have a more severe clinical course of hyaline membrane disease (HMD) may have a higher prevalence of patent ductus arteriosus (PDA). The exact reason for this is unclear.

In the low birth weight premature infant, the classic signs of a patent ductus arteriosus (PDA) are usually absent. The classic continuous murmur is rarely heard. A rough systolic murmur may be present along the left sternal border, but a small baby with a large patent ductus arteriosus (PDA) and significant pulmonary overcirculation may have no murmur. In that case, typically, precordial activity is increased and peripheral pulses are bounding. The increased precordial activity is caused by the large left ventricular stroke volume. Bounding pulses are caused by the relatively low systemic arterial blood pressure due to the continuous runoff of blood from the aorta into the pulmonary artery.

The diagnosis of patent ductus arteriosus (PDA) is almost always based on careful clinical evaluation, including physical examination showing the characteristic murmur, typical electrocardiographic (ECG) abnormalities, radiographic changes, and echocardiographic/Doppler findings.

Echocardiography is the primary diagnostic study used to evaluate and diagnose patent ductus arteriosus (PDA). Chest radiography may provide some helpful information. Laboratory tests are generally not helpful in the workup of patent ductus arteriosus (PDA). Magnetic resonance angiography and cardiac computed tomography are alternative, more novel, diagnostic tools.

CBC and metabolic panel

A complete blood cell (CBC) count with differential and a chemistry profile are obtained to determine the overall health of the child. However, findings are usually within reference ranges in patients with this condition. Polycythemia may be present if the child has other congenital heart defects.

Pulse oximetry/ABG

Pulse oximetry/arterial blood gas (ABG) analysis usually demonstrate normal saturation because of pulmonary overcirculation. A large ductus arteriosus could cause hypercarbia and hypoxemia from congestive heart failure (CHF) and air space disease (atelectasis or intra-alveolar fluid/pulmonary edema).

In the event of pulmonary artery hypertension (PAH), right-to-left intracardiac shunting of blood, hypoxemia, cyanosis, and acidemia may be present.

The echocardiographic findings are typically diagnostic for patent ductus arteriosus (PDA). High velocity jets of turbulent flow in the pulmonary artery can be reliably detected by color flow Doppler imaging; this technique is sensitive in detecting even the small PDA. Relying on alternative imaging techniques to make the diagnosis of this condition is unusual. Additionally, echocardiography provides important diagnostic information regarding associated congenital cardiovascular malformations.

By 2-dimensional (2-D) echocardiography, the aortic end of the patent ductus arteriosus (PDA) is localized first, and then it is tracked back to the pulmonary artery. Precisely documenting the size, shape, and course of the ductus is difficult.

The patent ductus arteriosus (PDA) can be seen most easily in the parasternal short axis view and from the suprasternal notch. The classic patent ductus arteriosus (PDA) connects the junction of the main pulmonary artery and the left pulmonary artery with the aorta just below and opposite the left subclavian artery.

If no other abnormalities are present, Doppler echocardiography reveals continuous flow from the aorta into the main pulmonary artery. If the magnitude of the left-to-right shunt is large, continued flow around the aortic arch into the ductus arteriosus in diastole and flow reversal in the descending aorta are evident. Also, variable levels of continuous flow in the branch pulmonary arteries related to the magnitude of the shunt are observed. As the shunt magnitude increases, increased flow in the pulmonary veins is evident and the left atrium enlarges. With a small or moderate-sized patent ductus arteriosus (PDA), the left ventricular size is often normal, but as shunt magnitude increases, the left ventricular diastolic size also increases. (Qp/Qs can be calculated using Doppler velocity and left ventricular/right ventricular (LV/RV) outflow tract dimensions.)

One study evaluated the internal color Doppler diameter of the PDA and the pulsed Doppler flow pattern in 197 echocardiograms from 104 infants (gestational age < 31 wk). The data noted that while ductal diameter varied widely, it was significantly associated with flow patterns. Because results from the 2 methods may result in different treatment decisions, the use of both echocardiographic parameters may be helpful in managing preterm infants with PDA.[3]

Findings on chest radiographs range from normal to those consistent for congestive heart failure (CHF). Cardiomegaly may be present with or without CHF.

If significant left-to-right shunt through the patent ductus arteriosus (PDA) is present, the pulmonary arteries, pulmonary veins, left atrium, and left ventricle are enlarged on chest films. Also, the ascending aorta may be prominent.

Usually, chest radiographic findings are normal until the magnitude of the ratio of pulmonary to systemic circulation (QP/QS) exceeds 2:1. Prominence of the main pulmonary artery segment is an early sign of increased pulmonary artery pressure and flow. With marked pulmonary overcirculation, pulmonary edema may occur. Accentuated peripheral pulmonary vascular markings and increased pulmonary venous markings may be noted. In elderly individuals, the patent ductus arteriosus (PDA) may calcify and may be visible on a standard radiograph.

Studies have shown that chest radiographs have limited predictive value in determining which infants will benefit from ligation.

With a small patent ductus arteriosus (PDA), the electrocardiographic (ECG) findings are typically normal. Left ventricular hypertrophy may be present with a larger PDA. Left atrial enlargement may also be present with large shunts. In the presence of significant pulmonary hypertension, there may be evidence of right ventricular hypertrophy.

In the neonate, especially the premature neonate with a large patent ductus arteriosus (PDA), T-wave inversion and ST segment depression may be present, suggesting ischemia or a supply-demand mismatch. This is thought to be related to increased myocardial work due to the left-to-right shunt and pulmonary overcirculation in the face of low aortic and coronary diastolic blood pressure due to the runoff of blood from the aorta into the pulmonary arteries.

Cardiac catheterization and angiography is not indicated for the uncomplicated patent ductus arteriosus (PDA). Color-flow Doppler mapping is more sensitive than cardiac catheterization in detecting a small patent ductus arteriosus (PDA). However, cardiac catheterization may be required for confirmation of clinical diagnosis in children with pulmonary hypertension and/or associated congenital cardiovascular malformations; response to pulmonary vasodilators can be important in planning operative intervention.

Cardiac catheterization may be used as a therapeutic procedure for coil embolization/occluder and to demonstrate the following:

• The shunt

• The amount of the shunt

• The pulmonary pressure

• Other coexisting cardiac abnormalities

During right heart catheterization, the measured oxygen saturation is increased in the pulmonary artery, except in Eisenmenger syndrome. The shunt (Qp/Qs) and the pulmonary vascular resistance (PVR) can be calculated to determine the size of the ductus and the presence of pulmonary vascular pathology.

Selective angiography is the definitive tool for determining the presence and size of the ductus. Angiography is also used to define the intracardiac anatomy when other defects are suspected.

Very rarely, a biopsy may be performed in severe cases. Histologic findings include the following:

• The walls of the ductus contain intima, media, and adventitia

• The medial layer of the structure is composed of longitudinal smooth muscle in the inner layer and circumferentially arranged smooth muscle in the outer layers; this is in contrast to true arterial structures, which contain a medium primarily composed of circumferential elastic fibers; these layers of smooth muscle contain concentric loose lamina of elastic tissue and a network of tiny thin-walled vessels.

• The intimal layer is irregularly thickened and contains a considerable amount of mucoid material

Spontaneous closure of the patent ductus arteriosus (PDA) is common. If significant respiratory distress or impaired systemic oxygen delivery is present, therapy is usually prudent. Intravenous (IV) indomethacin (or the newer preparation of IV ibuprofen) is frequently effective in closing a patent ductus arteriosus (PDA) if it is administered in the first 10-14 days of life. Other options are catheter closure (see Cardiac Catheterization) and surgical ligation, which entails a thoracotomy (see Surgical Ligation) (see the following image).

Diagram illustrating the patent ductus arteriosus.

Medical management also consists of amelioration of congestive heart failure (CHF) symptoms. CHF is an indication for closure of the patent ductus arteriosus (PDA) in infancy. If medical therapy is ineffective, urgent intervention to close the structure should be undertaken.

All patent ductus arteriosus (PDA) should be closed because of the risk of bacterial endocarditis associated with the open structure. Over time, the increased pulmonary blood flow precipitates pulmonary vascular obstructive disease, which is ultimately fatal.

Identification of additional cardiac malformations, such as coarctation or interrupted aortic arch or pulmonary atresia, is the most important requirement before pharmacologic or surgical closure of the patent ductus arteriosus (PDA). When surgical ligation is not indicated, prostaglandin inhibitors (eg, nonsteroid antiinflammatory drugs [NSAIDs]) are used to close the ductus arteriosus.

A ductal dependent lesion requires the persistence of a patent ductus arteriosus (PDA) to ensure adequate pulmonary blood flow.

Prehospital and emergency department care

General measures in prehospital and emergency department (ED) care for a patient with suspected patent ductus arteriosus (PDA) consist of supplemental oxygen for any hypoxia, pulmonary support, and supportive care. Other measures include sodium and fluid restriction as well as correction of any anemia.

Transfer

Transfer to a tertiary care center is mandatory for a patient in extremis presenting in florid CHF once stabilized with diuretics and positive pressure ventilation, as indicated.

Consultations

Consultation with a pediatric cardiologist and pediatric cardiovascular surgeon may be indicated.

Because patients presenting with a patent ductus arteriosus (PDA) are usually asymptomatic, no acute management is needed. However, until the patency of the ductus is corrected, administer antibiotics in patients during instances of high exposure to bacteremia (eg, instrumentation, dental procedures), as recommended by the American Heart Association for the prevention of bacterial endocarditis.[4]

Conservative standards include adaptation of ventilation by lowering inspiratory time and giving more positive end expiratory pressure (PEEP).[5] Furthermore, fluid restriction that does not exceed 130 mL/kg/d beyond day 3 is also used. This has been found to have a high closure rate of patent ductus arteriosus (PDA).

In infants who present with congestive heart failure (CHF), the standard treatment of digoxin and diuretic therapy usually palliates the condition. These children can be treated until they are several years old and are good candidates for ductal closure. When medical treatment of congestive heart failure fails in infants, the patients are referred early for surgical closure of the structure.

Closure of the patent ductus arteriosus (PDA) is stimulated by administration of prostaglandin synthesis inhibitors, such as indomethacin or aspirin, which is effective in premature infants (see Pharmacologic Management and Medication). Indomethacin (0.1 mg/kg body weight) is administered orally at 8-hour intervals. This treatment is particularly valuable in premature infants presenting with respiratory distress syndrome complicated by left-to-right shunting through the ductus.

One study concluded that B-type natriuretic peptide can be used to guide treatment, reducing the number of primary indomethacin doses.[6]

Additionally, a study of 50 preterm infants born at less than 33 weeks’ gestation found that obtaining N-terminal-pro-brain natriuretic peptide (NT-proBNP) levels on day 2 of life may be an effective guide for early targeted indomethacin therapy for PDA in preterm infants. This method may reduce later onset of hemodynamic significant PDA and unnecessary exposures to indomethacin.[7]

The premature neonate with a significant patent ductus arteriosus (PDA) is usually treated with intravenous (IV) indomethacin or ibuprofen.[8] This has been quite successful in most patients. Whether results with IV indomethacin are superior to those with surgical closure of the patent ductus arteriosus (PDA), even in the premature neonate in whom the safety of the surgery is a concern, is unclear.[9]

IV indomethacin was the standard drug treatment. Then, IV ibuprofen was approved by the US Food and Drug Association (FDA). Although ibuprofen and indomethacin are equally effective, other differences are noted: Indomethacin appears to decrease the incidence of intraventricular hemorrhage, whereas ibuprofen has less renal toxicity.

Indomethacin (Indocin)

Indomethacin has proven efficacious, resulting in twice the spontaneous closure rate.[10] McCarthy et al demonstrated the successful effects of indomethacin therapy on patent ductus arteriosus (PDA) in 4 newborns with a birth weight of 1500-2075 g who were born at a gestational age (GA) of 35 weeks or more.[11]

Watanabe et al evaluated indomethacin therapy in 13 infants with patent ductus arteriosus (PDA) complicated by congenital heart disease and reported closure in 4 of 7 infants with a birth weight of 2500 g or more.[12] Indomethacin was shown to be successful in both cases; however, the ductus may reopen days or weeks later. Prophylactic indomethacin was also found to reduce the incidence of severe grades of intracranial hemorrhage. Side effects of indomethacin include cerebral vasoconstriction.[12]

These drugs cause adverse renal effects, because renal perfusion and diuresis in early neonatal life are strongly influenced by the effects of prostaglandins on the afferent glomerular arterioles.

Ibuprofen (NeoProfen)

Prophylactic ibuprofen is also widely used. The dose used for ibuprofen is 10 mg/kg bolus followed by 5 mg/kg/d for 2 additional days.

When compared with indomethacin, ibuprofen is associated with a lower risk of oliguria in preterm infants. However, one study showed an increased risk of pulmonary hypertension in patients. The Cochrane evaluation on ibuprofen prophylaxis concluded that although prophylactic ibuprofen use reduces the incidence of patent ductus arteriosus (PDA) on day 3, potential adverse effects should be further addressed that also look at neurodevelopmental outcomes.[13]

Patent ductus arteriosus (PDA) closure is gestation dependent, with a cumulative closure rate of 65%. A similar proportion of infants had patent ductus arteriosus (PDA) closure following first and second courses of ibuprofen, regardless of gestation, suggesting that a second course of ibuprofen may be effective in closing a patent ductus arteriosus (PDA), obviating the need for surgery.[14]

Studies comparing indomethacin vs ibuprofen

A meta-analysis by Ohlssen et al found ibuprofen is as effective as indomethacin in closing a patent ductus arteriosus (PDA) and reduces the risk of necrotizing enterocolitis and transient renal insufficiency associated with indomethacin.[15]

A meta-analysis by Jones et al confirmed that both indomethacin and ibuprofen treatments promote patent ductus arteriosus (PDA) closure better than placebo.[16] Ibuprofen and indomethacin appear to be equally effective, with similar rates of complications after therapy except for the development of chronic lung disease (30% greater risk in ibuprofen treatment arm). However, the investigators did not discuss if chronic lung disease might have reflected selection bias or if the degree of chronic lung disease in these patients resulted in poorer long-term outcomes.[16]

Diuretic agents

Although diuretics and fluid restriction have been recommended for the treatment of symptomatic neonates, no rigorously collected data support this approach. In fact, a systematic review of furosemide use in preterm neonates with respiratory distress syndrome showed no long-term benefits and an increased risk of symptomatic patent ductus arteriosus (PDA).[17]

Infants with signs of failure may be treated initially with digoxin and diuretic therapy, but interruption of the ductus is required for definitive treatment.

The use of the percutaneous route to close the patent ductus arteriosus (PDA) is becoming more common. Transcatheter occlusion is an effective alternative to surgical intervention and is becoming the treatment of choice for most cases of patent ductus arteriosus (PDA) in children and adults.[18, 19, 20, 21, 22]

Most patients with an isolated patent ductus arteriosus (PDA) can have successful treatment by catheterization after the first few months of life.

After the first birthday, the most common treatment for a patent ductus arteriosus (PDA) is occlusion at cardiac catheterization. In fact, as catheterization techniques advance, the ability to close defects in smaller infants has also been reported with high levels of success. Over the last 4 decades, many techniques and devices have been used for patent ductus arteriosus (PDA) occlusion, although definitive closure rates do not approach those of surgery. Contraindications to catheter-based closure involve the size of the patient.

Gianturco spring occluding coils

Introduced in 1992, Gianturco spring occluding coils have been the most common device used for patent ductus arteriosus (PDA) occlusion for many years. The coils are delivered to the patent ductus arteriosus (PDA) via venous or arterial systems: 1-5 coils are placed in the ductus. In experienced hands with proper patient selection, this has become a procedure associated with high success and low morbidity. This method has been reported to be 75-100% effective but is limited to ductus that are only 4-5 mm in diameter. Coil occlusion is best suited to close a patent ductus arteriosus (PDA) with a minimal internal diameter of less than 2.5 mm. Fue et al showed that very high closure rates could be obtained in ducts less than 3 mm using coils, but that success significantly dropped when the ducts exceeded 3 mm.

Amplatzer duct occluder

More recently, the Amplatzer device has expanded the ability to close patent ductus arteriosus (PDA) at cardiac catheterization. This device is more reliable and easier to implant in a large patent ductus arteriosus (PDA) than spring occluding coils. The major disadvantage of the design is that the aortic part of the device can protrude into the descending aorta and partly obstruct the lumen, especially in infants. However, the Amplatzer duct occluder II (ADO II), a nitinol flexible mesh with a symmetrical design to provide high conformability, has been approved in Europe for treatment of all types of patent ductus arteriosus (PDA).[23]

Rashkind ductus occlusion device

The Rashkind ductus occlusion device consists of a 2-umbrella system delivered to the ductus in either the transvenous pathway or transarterial pathway. This therapy has a reported occlusion rate of 83%. Although used internationally, it is not approved for use in the United States.

Postcatheterization risks

Typically, complete occlusion is achieved at catheterization. Occasionally, a tiny residual left-to-right shunt remains at the end of the procedure, which closes by thrombus formation over the following days or weeks. Left-to-right shunt rarely persists through a partially occluded patent ductus arteriosus (PDA). Usually, the magnitude of the shunt is significantly smaller than before occlusion. Due to concerns about the long-term risk of endocarditis, this residual defect should be closed. Often, this can be accomplished with a second catheter procedure. Rare reports describe association of a persistently patent ductus after occlusion attempts with hemolysis or endocarditis.

Procedural risks of patent ductus arteriosus (PDA) occlusion by catheter are few and largely influenced by the experience of the physician performing the procedure. These risks include embolization of the device being used to occlude the patent ductus arteriosus (PDA), blood vessel injury, access site bleeding, infection, and stroke, among others. In the case of device embolization, the device can usually be retrieved by transcatheter techniques, and a second device can be successfully placed in the patent ductus arteriosus (PDA).

Surgical ligation or surgical ligation and division remain the standard treatment of large patent ductus arteriosus (PDA) that require treatment in infancy (see the following image). This is a particularly successful, low-risk procedure in the hands of an experienced pediatric cardiovascular surgeon. This is true even in the smallest premature babies. (See also Patent Ductus Arteriosus Surgery.)

Diagram illustrating ligation of the patent ductus arteriosus.

Ligation (with or without division of the patent ductus arteriosus [PDA]) without cardiopulmonary bypass can be performed through a left posterolateral thoracotomy. Video-assisted thoracoscopic surgery (VATS) ligation of patent ductus arteriosus (PDA) is less invasive than the posterolateral thoracotomy and has been shown to be safe and effective.[24]

Indications

With rare exceptions, the presence of a patent ductus arteriosus (PDA) is an indication for surgical closure. Clearly, attention must be paid to the existence of other congenital heart lesions that impair pulmonary blood flow. In these patients, all attempts should be made to preserve ductal flow until a more permanent palliative shunt can be constructed or definitive repair can be undertaken. Very small premature infants still require surgical closure.

In the infant, repair may be urgent for the symptomatic patient with evidence of cardiac or respiratory failure not adequately controlled with medications, or it may be delayed in the patient who is asymptomatic or well controlled on medical therapy.

Postoperative results are best if the patent ductus arteriosus (PDA) is closed while the patient is younger than 3 years.[25] An increased incidence of elevated pulmonary vascular resistance (PVR) and pulmonary hypertension occurs if the lesion closed in those older than 3 years.

Thus, indications for surgical treatment include the following:

• Failure of indomethacin treatment

• Contraindications to medical therapy (eg, thrombocytopenia, renal insufficiency)

• Signs and symptoms of congestive heart failure (CHF)

• Patent ductus arteriosus (PDA) found in an older infant

• Infants found to have an asymptomatic patent ductus arteriosus (PDA) after the neonatal period should undergo surgical ligation preferably before the age of 1 year to prevent future complications of a patent ductus arteriosus (PDA)

• Ductal closure is indicated for cardiovascular compromise (ie, pulmonary complications) and for reduction of the risk of infective endocarditis (subacute bacterial endocarditis)

Contraindications

The primary contraindication to repair is severe pulmonary vascular disease. If transient intraoperative occlusion of the patent ductus arteriosus (PDA) does not decrease elevated pulmonary arterial pressures with a subsequent increase in aortic pressure, then the closure must be undertaken carefully and may be contraindicated. Closure of the ductus does not reverse preexisting pulmonary vascular disease.

A subset of associated cardiac anomalies—so-called ductal-dependent lesions—depend on flow through the patent ductus arteriosus (PDA) to maintain systemic blood flow. Premature closure of the ductus without concurrent repair of the following defects is contraindicated and may be fatal:

• Aortic valve atresia

• Mitral valve atresia with hypoplastic left ventricle

• Pulmonary artery hypoplasia

• Pulmonary atresia

• Severe coarctation of the aorta

• Tricuspid atresia

• Transposition of the great arteries

Other contraindications to surgical closure include concurrent uncontrolled sepsis and an inability of the patient to tolerate general anesthesia.

Medical vs surgical therapy

Although indomethacin therapy is preferred in most intensive care nurseries (NICUs) as the first-line approach to effect patent ductus arteriosus (PDA) closure, the benefits of this approach over surgical ligation are not obvious. In most studies that attempt to evaluate differences in the outcomes for indomethacin therapy and surgical closure, results are similar. A Cochrane review failed to demonstrate that the net harm-to-benefit ratio favored either surgical ligation or medical therapy.[8] Observational studies suggest that surgical ligation is associated with higher likelihood of chronic lung disease, retinopathy of prematurity, and neurosensory impairment. These data may be questionable, because surgical ligation is not available in every nursery, whereas medical therapy is widely available.

A meta-analysis by Weisz et al did suggest that compared with pharmacologic treatment, surgical ligation for patent ductus arteriosus in preterm infants is associated with a reduced mortality rate but also with an increased morbidity risk. Again, however, the results were uncertain. In the report, derived from 39 cohort studies and 1 randomized, controlled trial, the investigators found that in infants born at less than 32 weeks’ gestation, the mortality rate in those who underwent ligation for patent ductus arteriosus was about half that of infants who were treated with medication for the condition.[26, 27]

In contrast, the incidence of neurodevelopmental impairment (NDI), chronic lung disease, and severe retinopathy of prematurity was increased in infants who underwent ligation, with adjusted odds ratios of 1.54, 2.51, and 2.23, respectively. However, the investigators were unable to draw conclusions from the meta-analysis because almost none of the cohort studies took into account survival bias or considered important confounders, such as ventilator dependence, sepsis, or intraventricular hemorrhage, that may have been present prior to ligation.[26, 27]

Complications

Complications of surgical ligation are mostly related to the left lateral thoracotomy. Surgical morbidity and mortality rates are negligible, and early postoperative complications are associated with other complications of prematurity. However, possible injury to the aorta, pulmonary artery,[28] and other structures should be noted.

The results from a study of 125 premature infants found that while PDA ligation was well tolerated overall, a high risk of neurological disability or death from bronchopulmonary dysplasia at 1 year was noted. Increased mortality at 1 year was also associated with increasing preoperative fractional inspired oxygen (FiO2) and lack of prior treatment with cyclooxygenase inhibitors.[29]

Typically, hospitalization following treatment for patent ductus arteriosus (PDA) is minimal. Patients who have catheter closure of patent ductus arteriosus (PDA) are usually sent home on the day of the procedure. Even patients who have standard surgery with a thoracotomy rarely are hospitalized for longer than 2 or 3 days.

The appropriate care and length of hospitalization of premature neonates with a patent ductus arteriosus (PDA) are primarily determined based on abnormalities of other organ systems. However, babies who have effective closure of patent ductus arteriosus (PDA) appear to have shorter hospital stays than babies whose patent ductus arteriosus (PDA) remains a problem.

Complications of untreated patent ductus arteriosus (PDA) include bacterial endocarditis, late congestive heart failure (CHF), and the development of pulmonary vascular obstructive disease. Patent ductus arteriosus (PDA) can complicate other circulatory or ventilatory abnormalities, such as the following:

• Aortic rupture

• Eisenmenger physiology

• Left heart failure

• Myocardial ischemia

• Necrotizing enterocolitis

• Pulmonary hypertension

• Right heart hypertrophy and failure

Prostaglandin E1 (PGE1) should be used to maintain patency of the ductus arteriosus once it is established that a ductal dependent lesion exists. However, PGE is a pulmonary vasodilator and could cause exacerbation of CHF by means of increasing pulmonary blood flow.

Parents of children with this lesion should be aware that patent ductus arteriosus (PDA) does not have any significant inheritance pattern.

Once the patent ductus arteriosus (PDA) is closed, no special limitations or care is necessary. No exercise restriction is required in the absence of pulmonary hypertension.

Most physicians recommend antibiotic prophylaxis at times of risk of bacteremia for 6-12 months following closure, whether by catheter or surgery. (Specific recommendations for prophylactic antibiotics can be found in any current infectious disease or antibiotic reference, or refer to the American Heart Association recommendations.[4] )

Although rare reports exist of recanalization and recurrence of a left-to-right shunt after patent ductus arteriosus (PDA) ligation, the risk is extremely low. If a patent ductus arteriosus (PDA) has been closed by interventional radiologic techniques, obtaining follow-up echocardiograms echocardiography 2-3 weeks after the procedure until complete closure is confirmed is wise.

Medication use in patent ductus arteriosus (PDA) is based upon the clinical status of the patient.

In the presence of symptoms of pulmonary overcirculation or pulmonary hypertension related to a patent ductus arteriosus (PDA), closing the lesion is usually most prudent; therefore, anticongestive therapy is not discussed.

Prostaglandins are utilized to maintain the patency of the ductus arteriosus until surgical ligation is performed. When surgical ligation is not indicated, prostaglandin inhibitors (eg, nonsteroid antiinflammatory drugs [NSAIDs]) are used to close the ductus arteriosus.

Intravenous (IV) indomethacin or IV ibuprofen is used to treat patent ductus arteriosus (PDA) in the neonate and in premature infants. The dose used for ibuprofen is 10 mg/kg bolus followed by 5 mg/kg/d for 2 additional days. (IV ibuprofen became available in the United States on June 2009.)

Ibuprofen was initially thought to have less adverse effects, such as a decreased incidence of oliguria, gastrointestinal (GI) toxicity, and cerebral hypoperfusion. The use of ibuprofen has been shown to increase the incidence of pulmonary hypertension and chronic lung disease.

A Cochrane database review showed no statistically significant difference in closure between ibuprofen and indomethacin.[8] A decision to use one drug versus another should be based upon the infant's presentation and comorbidities.

A similar Cochrane database article that looked at the initial treatment of symptomatic patent ductus arteriosus (PDA) in preterm infants showed no difference in risks or benefits of surgery versus the use of cyclooxygenase inhibitors.[30]

In a prospective, randomized, controlled trial, Attridge et al found that patients administered b-type natriuretic peptide (BNP) received fewer primary indomethacin doses compared with those who were not guided by BNP concentrations.[6] Renal toxicity is associated with indomethacin, and dose reduction guided by BNP may reduce this risk.[6]

Class Summary

Prostaglandins promote vasodilatation by direct effect on the vasculature and smooth muscle of the ductus arteriosus.

Alprostadil (Prostin VR Pediatric)

Alprostadil is used to maintain the patency of the ductus arteriosus when a cyanotic lesion or interrupted aortic arch presents in a newborn. Prostaglandin E1 (PGE1) is most effective in premature infants.

Class Summary

In the neonate, ductal patency appears to be related to continued production of prostaglandin. This is particularly true in the premature infant; therefore, prostaglandin inhibition can affect ductal closure. NSAIDs inhibit the production of prostaglandins by decreasing the activity of cyclooxygenase. The result is a functional closure of the patent ductus arteriosus (PDA) in 80% of patients.

Ibuprofen lysine injection (NeoProfen)

The mechanism of action of ibuprofen lysine injection that results in patent ductus arteriosus (PDA) closure in neonates is not known; however, ibuprofen is an inhibitor of prostaglandin synthesis. This agent is indicated to close a clinically significant PDA in premature infants who weigh between 500-1500 g at ≤ 32 weeks' gestational age when the usual medical management (eg, fluid restriction, diuretics, respiratory support) is ineffective.

Indomethacin (Indocin)

Indomethacin is indicated for patent ductus arteriosus (PDA) closure, as it promotes closure of the PDA and generally has an onset of action within minutes. Prostaglandins, especially E-type prostaglandins, maintain the patency of the ductus. Thus, inhibition of prostaglandin synthesis by indomethacin results in constriction of the ductus arteriosus.