Overview

The ductus arteriosus connects the descending aorta (just distal to the left subclavian artery) to the left pulmonary artery. In the fetus, it permits pulmonary arterial blood to bypass the unexpanded lungs and enter the descending aorta for oxygenation in the placenta. It normally closes soon after birth, but in some infants it does not close spontaneously, and there is continuous flow from the aorta to the pulmonary artery (i.e., left-to-right shunting).
Patent ductus arteriosus accounts for about 10 percent of cases of congenital heart disease. Its incidence is higher than average in pregnancies complicated by persistent perinatal hypoxemia or maternal rubella infection and among infants born at high altitude or prematurely.

A patient with patent ductus arteriosus and a moderate or large shunt has bounding peripheral arterial pulses, a widened pulse pressure, and a hyperdynamic left ventricular impulse. The first heart sound is normal. A continuous “machinery” murmur, audible in the second left anterior intercostal space, begins shortly after the first heart sound, peaks in intensity at or immediately after the second heart sound (thereby obscuring it), and declines in intensity during diastole. With a large shunt, mid-diastolic and systolic murmurs (from increased flow through the mitral and aortic valves, respectively) may be noted. If pulmonary vascular obstruction and hypertension develop, the continuous murmur decreases in duration and intensity and eventually disappears and a pulmonary ejection click and a diastolic decrescendo murmur of pulmonary regurgitation may appear.

With a small patent ductus arteriosus, the electrocardiogram and chest x-ray film are normal. With a large patent ductus arteriosus and substantial left-toright shunting, left atrial and ventricular hypertrophy are evident, and the chest film shows pulmonary plethora, proximal pulmonary arterial dilatation, and a prominent ascending aorta. The ductus arteriosus may be visualized as an opacity at the confluence of the descending aorta and the aortic knob. If pulmonary hypertension develops, right ventricular hypertrophy is noted. With two-dimensional echocardiography, the ductus arteriosus can usually be visualized, and Doppler studies demonstrate continuous flow in the pulmonary trunk. Catheterization and angiography make it possible to quantify the magnitude of shunting and the pulmonary vascular rsistance as well as visualize the ductus arteriosus.

A patent ductus arteriosus rarely closes spontaneously after infancy. A small patent ductus arteriosus causes no symptoms, and a person with a defect of this size can have a normal life expectancy. However, the presence of a small patent ductus arteriosus entails an elevated risk of infective endocarditis, which involves the pulmonary side of the ductus arteriosus or the pulmonary artery opposite the duct orifice, from which septic pulmonary emboli may arise. A patent ductus arteriosus of moderate size may cause no symptoms during infancy; during childhood or adulthood, fatigue, dyspnea, or palpitations may appear. In addition, the ductus arteriosus may become aneurysmal and calcified, which may lead to its rupture (37-40). With larger shunts, flow is markedly increased, which may precipitate left ventricular failure. Eventually, pulmonary vascular obstruction may develop; when the pulmonary vascular resistance equals or exceeds the systemic vascular resistance, the direction of shunting reverses. One third of patients with a patent ductus arteriosus that is not surgically repaired die of heart failure, pulmonary hypertension, or endarteritis by the age of 40 years, and two thirds die by the age of 60 years.

Surgical ligation of patent ductus arteriosus, generally accomplished without cardiopulmonary bypass, has an associated mortality of less than 0.5 percent. However, in patients with ductal aneurysmal dilatation or calcification, resection with cardiopulmonary bypass may be required. Because of the risk of endarteritis associated with unrepaired patent ductus arteriosus (estimated at 0.45 percent annually after the second decade of life) and the low risk associated with ligation, we recommend that even a small patent ductus arteriosus be ligated surgically or occluded with a percutaneously placed closure device. Once severe pulmonary vascular obstructive disease develops, surgical ligation or percutaneous closure is
contraindicated.

Pathophysiology, Frequency, Mortality, Sex, and Age

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

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. Most typically, it is a left aortic remnant. A right PDA can occur, or the ductus arteriosus can be present on both the right and the left. While a left ductus arteriosus is a normal structure during normal fetal development, the presence of a right ductus arteriosus usually is associated with other congenital abnormalities of the cardiovascular system, most typically involving the aortic arch or conotruncal development.


PATHOPHYSIOLOGY

A 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. The magnitude of the excess pulmonary blood flow is dependent on relatively few factors. The larger the internal diameter of the narrowest 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 controlled partially by the relationship of the pulmonary vascular resistance to the systemic vascular resistance.

If the systemic vascular resistance is high and/or the pulmonary vascular resistance is low, the flow through the ductus arteriosus is large. Beginning at the ductus arteriosus, the course of blood flow in a typical PDA with pulmonary overcirculation is as follows: PDA, pulmonary artery, pulmonary capillaries, pulmonary veins, left atrium, left ventricle, aorta, PDA. Therefore, a large left-to-right shunt through a PDA results in left atrial and left ventricular enlargement. Additionally, the pulmonary veins and the ascending aorta can be dilated with a sufficiently large PDA. Also, if little or no restriction exists at the level of the PDA, pulmonary hypertension results.

The ductus arteriosus is normally patent during fetal life. This patency is promoted by continual production of prostaglandin E2 (PGE2) by the ductus. Prostaglandin antagonism, such as maternal use of nonsteroidal anti-inflammatory medications, can cause fetal closure of the ductus arteriosus. This can be associated with severe fetal cardiovascular compromise.

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. This was first demonstrated by multiple experiments in the 1940s and has been confirmed subsequently. Even though 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.

Even though functional closure usually occurs in the first few hours of life, true anatomic closure, where the ductus loses the ability to reopen, may take several weeks. Cassels defined true persistence of the ductus arteriosus as a PDA present in infants older than 3 months.


FREQUENCY

In the US: The estimated incidence in children born at term is between 0.02% and 0.006% of live births. This incidence is increased in children who are born prematurely, children with a history of perinatal asphyxia, and, possibly, children born at high altitude. Perinatal asphyxia usually only delays the closure of the ductus, and, over time, the ductus typically closes without specific therapy.

MORTALITY/MORBIDITY

The low birthweight premature infant: As many as 20% of neonates with respiratory distress syndrome have a PDA. In babies who are less than 1500 g at birth, many studies show the incidence of a 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 birthweight neonates, are more likely to have problems related to PDA. Spontaneous closure of the PDA in premature neonates is common, but respiratory distress and impaired systemic oxygen delivery (congestive heart failure) often drive the need for therapy to effect ductal closure in this group. Low birthweight neonates with a PDA are more likely to develop chronic lung disease.

Otherwise healthy infants, children, adolescents, and adults: In the preantibiotic era, Campbell estimated the natural history mortality rates for untreated PDA to be 0.42% per year from age 2-19 years, 1.0-1.5% per year in the third decade, 2.0-2.5% per year in the fourth decade, and 4% per year in persons older than 40 years. Currently, with the availability of antibiotics to treat endocarditis and low-risk surgery and catheter techniques to obliterate the PDA, the mortality rate appears to be quite low except in the extremely premature infant.

SEX

The female-to-male ratio is 2:1 if not associated with other risk factors. In patients in whom the PDA is associated with a specific teratogenic exposure, such as congenital rubella, the incidence is equal between the sexes.

AGE

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.

Clinical Findings

HISTORY

The typical child with a PDA is asymptomatic.

• A history of premature birth, perinatal distress, or perinatal hypoxia may be present.


• Some series have suggested that children born at extreme altitude have an increased incidence of a persistent PDA.


• Occasionally, a history of feeding difficulties and poor growth during infancy, described as failure to thrive, is found. However, frank symptoms of congestive heart failure are rare.


• In the low birthweight premature infant, diagnosing a PDA on auscultation may be difficult. Babies that have a more severe clinical course of hyaline membrane disease may have a higher prevalence of PDA. The exact reason for this is unclear.

PHYSICAL

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

• 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. The second heart sound (S2) often is 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.
  
  
  • In 1898, Gibson described the classic murmur. Subsequently, the classic PDA murmur has been referred to as a machinery murmur, which is continuous. The murmur may be systolically accentuated. It is typically 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 across the mitral valve into the left ventricle, frequently is present. Also, since flow through the left ventricle into the aorta is increased, an aortic ejection murmur may be present. If the PDA is small, the amplitude of the murmur may increase with inspiration as pulmonary impedance drops.


• The peripheral pulses often are 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.


• In the low birthweight premature infant, the classic signs of a PDA are usually absent. The classic continuous murmur rarely is heard. A rough systolic murmur may be present along the left sternal border, but a small baby with a large 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. The 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.

CAUSES

• Familial cases of PDA have been recorded, but a genetic cause has not been determined.


• Several chromosomal abnormalities are associated with persistent patency of the ductus arteriosus. Implicated teratogens include congenital rubella (associated with PDA and pulmonary artery branch stenosis), fetal alcohol syndrome, maternal amphetamine use, and maternal phenytoin use.

Differential Diagnosis

• Aortopulmonary Septal Defect


• Coronary Artery Fistula


• Sinus of Valsalva Aneurysm


• Tetralogy of Fallot With Absent Pulmonary Valve

Other Problems to be Considered:

• Venous hum


• Coronary artery fistula to the right ventricle or right atrium


• Atrioventricular malformation

Imaging studies and other tests

IMAGING STUDIES

• Chest radiography
  
  
  
  • If significant left-to-right shunt through the PDA is present, the pulmonary arteries, pulmonary veins, left atrium, and left ventricle are enlarged. 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. With marked pulmonary overcirculation, pulmonary edema may occur. In elderly individuals, the PDA may calcify and be visible on a standard radiograph.


• Doppler echocardiography
  
  
  
  • The echocardiographic findings are typically diagnostic. Relying on alternative imaging techniques to make the diagnosis of PDA is unusual. By 2-dimensional echocardiography, the PDA can be seen most easily in the parasternal short axis view and from the suprasternal notch. The classic 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 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 PDA, the left ventricular size is often normal, but as shunt magnitude increases, the left ventricular diastolic size also increases.

OTHER TESTS

• Electrocardiogram
  
  
  
  • With a small PDA, the ECG findings are typically normal. Left ventricular hypertrophy may be present with a larger PDA. This is typically seen as tall R waves in the lateral precordial leads (V6).
  
  
  • In the neonate, especially the premature neonate with a large 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.

Treatment

MEDICAL CARE

The premature neonate with a significant PDA usually is treated with intravenous indomethacin. This has been quite successful in most patients. Whether results with intravenous indomethacin are superior to those with surgical closure of the PDA, even in the premature neonate in whom the safety of the surgery is a concern, is not clear. Recently, intravenous ibuprofen has been approved by the US Food and Drug Association (FDA) and may be equal in efficacy with indomethacin and possibly has fewer adverse effects.

• In the symptomatic neonate, diuretics and cautious fluid restriction may be sufficient for initial therapy if symptoms are mild and the baby is not extremely premature. Spontaneous closure is common. If significant respiratory distress or impaired systemic oxygen delivery is present, therapy is usually prudent. Intravenous indomethacin (or the new preparation of intravenous ibuprofen) is frequently effective in closing a PDA if it is administered in the first 10-14 days of life. (Another option is surgical ligation, discussed in Surgical Care.)


• After the first birthday, the most common treatment for a 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 PDA occlusion. For many years, the most common device used for PDA occlusion is a Gianturco spring occluding coil. In experienced hands with proper patient selection, this has become a procedure associated with high success and low morbidity. Coil occlusion is best suited to close PDAs with a minimal internal diameter of less than 2.5 mm. Success is usual with a PDA diameter of 2.5-3 mm, but larger PDAs probably are best served by alternate techniques.
  
  
  • More recently, the Amplatzer PDA device has expanded the ability to close PDAs at cardiac catheterization. This device is more reliable and easier to implant in larger PDAs than spring occluding coils. Other occlusion devices remain under investigation. Most patients with an isolated PDA can have successful treatment by catheterization after the first few months of life.
  
  
• 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 PDA. Usually, the magnitude of the shunt is significantly smaller than prior to 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 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 PDA, blood vessel injury, and stroke. In the case of device embolization, the device usually can be retrieved by transcatheter techniques, and a second device can be successfully placed in the PDA.

SURGICAL CARE

Surgical ligation or surgical ligation and division remain the standard treatment of large PDAs that require treatment in infancy. This is a particularly successful procedure in the hands of an experienced pediatric cardiovascular surgeon. The techniques are reviewed in Patent Ductus Arterious: Surgical Perspective.

When performed by an experienced pediatric cardiac surgeon, PDA ligation is a low-risk procedure with excellent results. This is true even in the smallest premature babies. The risks include hemorrhage, vessel damage, ligation of the wrong vessel (left pulmonary artery or aorta), recurrent laryngeal nerve or phrenic nerve damage, or infection.

While indomethacin therapy is preferred in most intensive care nurseries as the first-line approach to effect 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.

CONSULTATIONS

• Pediatric cardiologist


• Pediatric cardiovascular surgeon

Medication

In the presence of symptoms of pulmonary overcirculation or pulmonary hypertension related to a PDA, closing the PDA is usually most prudent; therefore, anticongestive therapy is not discussed. Indomethacin IV is used to treat PDA in the neonate. Successful use of ibuprofen IV was described in a recent study; however, the IV dosage form is not yet marketed in the United States.

Drug Category: Prostaglandin inhibitors -- 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.

Drug Name	Indomethacin (Indocin) -- This is the only medication indicated for PDA closure available in the United States. 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.
Adult Dose	Not indicated
Pediatric Dose	Many dosage regimens exist, and dose is dependent on postnatal age (PNA) at time of first dose; one example is as follows: PNA <48 hours: 0.1 mg/kg IV q12h for 3 doses PNA 2-7 days: 0.2 mg/kg IV q12h for 3 doses PNA >7 days: 0.25 mg/kg IV q12h for 3 doses
Contraindications	Documented hypersensitivity; GI bleeding; anuria
Interactions	Coadministration with aspirin increases risk of inducing serious NSAID-related adverse effects; probenecid may increase concentrations and, possibly, toxicity of NSAIDs; may decrease effects of hydralazine, captopril, and beta-blockers; may decrease diuretic effects of furosemide and thiazides; may increase PT when taking anticoagulants (watch for signs of bleeding); may increase risk of methotrexate toxicity; phenytoin levels may be increased when administered concurrently
Pregnancy	D - Unsafe in pregnancy
Precautions	Caution with intraventricular hemorrhage (particularly if active hemorrhage), renal failure, thrombocytopenia, and severe hyperbilirubinemia; increases risk of acute renal failure in patients with preexisting renal disease or compromised renal perfusion; reversible leukopenia may occur (discontinue if persistent leukopenia, granulocytopenia, or thrombocytopenia); adjust dosage interval with renal insufficiency

Inpatient/Outpatient Care, Complications, Prognosis, and Special Concerns

FURTHER INPATIENT CARE

Typically, hospitalization following treatment for PDA is minimal. Patients who have catheter closure of PDA usually are 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 hospitalization of premature neonates with a PDA primarily are determined based on abnormalities of other organ systems. However, babies who have effective closure of PDA appear to have shorter hospital stays than babies whose PDA remains a problem.

FURTHER OUTPATIENT CARE

Once the PDA is closed, no special limitations or care is necessary. Most physicians recommend antibiotic prophylaxis at times of risk of bacteremia for 6-12 months following closure, whether by catheter or surgery.

COMPLICATIONS

• Endocarditis


• Congestive heart failure


• Pulmonary vascular obstructive disease


• Aortic rupture

PROGNOSIS

• Typically, following PDA closure, patients experience no further symptoms and have no further cardiac sequelae.


• Premature infants who had a significant PDA are more likely to develop bronchopulmonary dysplasia.

SPECIAL CONCERNS

• Some canine breeds, such as certain strains of poodle, have a large prevalence of PDA.