Elizabeth H. Stephens1, Paul Tannous2, Carl L. Backer3, and Constantine Mavroudis4 1Mayo Clinic, Rochester, MN, USA 2Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL, USA 3UK HealthCare Kentucky Children’s Hospital, Lexington, KY, USA 4Peyton Manning Children’s Hospital, Indianapolis, IN, USA The patent arterial duct is an arterial connection between the pulmonary artery and the aorta. It is normally present in the fetus to direct the pulmonary arterial blood to the aorta. The patent arterial duct usually closes shortly after birth, and the term “patent arterial duct” refers to the pathologic persistence of the ductal lumen after birth. The ligation of a patent arterial duct by Dr. Robert E. Gross in 1938 at Boston Children’s Hospital is often cited as the first successful congenital heart procedure [1]. This landmark event truly ushered in the modern era of congenital heart surgery. At that time, Maude Abbott [2] had recently demonstrated in a series of 92 autopsy patients with a patent arterial duct that one‐fourth of the patients died of bacterial endocarditis of the pulmonary artery, and one‐half died of cardiac decompensation at an average age of 24 years. The child that Gross operated on was 7 years of age and following the procedure her diastolic blood pressure went from 38 mmHg to 80 mmHg. Gross was 33 years old at the time and waited to do the operation until the month of August when his chief, Dr. William Ladd, was on summer vacation. Patent arterial duct is also the first congenital cardiac lesion to have been corrected with the use of transcatheter techniques. In 1967 Porstmann [3] used a polyvinyl alcohol foam plug placed with a catheter to close a patent arterial duct. Now transcatheter closure is commonplace, and very few patients have surgical intervention. The patent arterial duct was previously termed patent ductus arteriosus. In keeping with recent revisions of formerly Latin medical terminology, we now prefer the term patent arterial duct. The patent arterial duct (sometimes referred to as the “ductus of Botalli,” especially in Europe) [4] is a normal fetal structure arising from the left sixth aortic arch. The arterial duct is a normal in utero vascular connection between the main pulmonary artery and the upper descending thoracic aorta just distal and opposite to the origin of the left subclavian artery (Figure 11.1). The duct may rarely be bilateral (right and left duct) or absent (tetralogy of Fallot with absent pulmonary valve). In infancy the length of the duct varies from 2 mm to 8 mm with a diameter of 4–12 mm, averaging 7 mm. The pulmonary end of the duct typically tapers and is narrower than the aortic end. The histologic structure of the arterial duct differs from other arteries. The media is deficient in elastic fibers, being composed of poorly arranged smooth muscle cells in a spiral configuration. The intima is thickened with an increased number of mucoid‐filled structures. The smooth muscle is especially sensitive to prostaglandin‐mediated relaxation and PO2‐induced constriction. During fetal development approximately 60% of the right ventricular blood flow is diverted from the high‐resistance pulmonary vascular bed through the patent arterial duct into the aorta. Circulating prostaglandins actively maintain ductal patency during the fetal period. At birth an elevated arterial PO2, brought about by breathing, inhibits prostaglandin synthetase, which leads to decreased prostaglandin levels and results in ductal constriction [5]. In full‐term infants this ductal closure occurs in three phases: (i) initial smooth muscle constriction narrowing the ductal lumen; (ii) loss of ductal responsiveness to prostaglandin vasodilation; and (iii) irreversible anatomic remodeling resulting in permanent occlusion [6]. Initial constriction of the duct produces a zone of hypoxia in the media, leading to local smooth muscle cell death and production of vascular endothelial cell growth factors (VEGF) [6]. Permanent closure of the arterial duct requires loss of cells from the muscular media and development of neointimal mounds, composed in part by proliferating endothelial cells stimulated by the VEGF. The fibrosed arterial duct is then called the arterial ligament. Figure 11.1 Patent arterial duct as visualized from a left anterior oblique view. The typical duct extends as illustrated from the junction of the main pulmonary artery with the left pulmonary artery to the descending thoracic aorta just distal to the left subclavian artery. Ao, aorta; IA, innominate artery; LCCA, left common carotid artery; LPA, left pulmonary artery; LSA, left subclavian artery; PA, pulmonary artery; PDA, patent arterial duct. Source: Reprinted with permission from Hillman ND et al., in Pediatric Cardiac Surgery, Philadelphia, PA: Mosby, 2003, pp. 223–233. Ductal morphology can be quite variable when there is an associated congenital heart lesion. In isolated patent arterial duct the angle between the superior margin of the duct and aorta is acute, and the duct is in smooth continuity with the descending aorta (Figure 11.2). In patients with ductal‐dependent pulmonary circulation (i.e., pulmonary atresia), the proximal angle is much less acute and may be obtuse. Patent arterial duct accounts for 3–5% of all congenital heart defects. Patent arterial duct is twice as common among females [7] and occurs in approximately 1 in 1600 term live births [8]. Maternal rubella virus during the first trimester is associated with an increased incidence of patent arterial duct [9]. The incidence of patent arterial duct in preterm infants is increased in comparison to full‐term infants. The overall incidence of patent arterial duct in preterm infants is 20–30%. The incidence rises sharply with earlier gestational age and lower birth weight. In infants at gestational age 34–36 weeks the incidence of patent arterial duct is 21%, at 31–33 weeks it is 44%, and at 28–30 weeks it is 77% [10]. In preterm infants, immature ductal tissue is less sensitive to PO2‐mediated constriction and more sensitive to prostaglandin vasodilation [11]. In addition, premature infants lack the muscular layer in the pulmonary arteries that can constrict to limit pulmonary blood flow. In preterm infants, a patent arterial duct may contribute to morbidity from necrotizing enterocolitis, abnormal cerebral blood flow, respiratory distress syndrome, and chronic lung disease. Retrograde blood flow in the descending aorta in diastole leads to decreased systemic flow and predisposition to end‐organ ischemia (renal failure, necrotizing enterocolitis). In term infants and older children, a small patent arterial duct may be hemodynamically insignificant and detected only by echocardiography. A large nonrestrictive duct with no other congenital cardiac defects produces a large left‐to‐right shunt with left atrial dilation, left ventricular volume overload, and progressive congestive heart failure. Left untreated, a large patent arterial duct may lead to pulmonary arteriolar hypertension, with the eventual development of a right‐to‐left shunt and Eisenmenger’s physiology. Significant elevation in pulmonary vascular resistance may develop at as early as 6 months of life, resulting in suprasystemic pulmonary artery pressures. Other complications, reported less frequently today than in historical series, include infective endocarditis [2], ductal aneurysm [12], aortic aneurysm, pulmonary artery aneurysm, and aortic dissection. Figure 11.2 Normal angulation between the neonatal arterial duct and the descending aorta (black arrowhead). No aortic flow splitter is formed because the fetal duct is continuous with the descending aorta. Aortic isthmus (i) is the segment between the duct and the left subclavian artery. Source: Reprinted with permission from Hillman ND et al., in Pediatric Cardiac Surgery, Philadelphia, PA: Mosby, 2003, pp. 223–233. Functional closure of the arterial duct usually occurs within a few hours of birth in term infants and anatomically it is usually permanently closed within 6 weeks [7]. In reviewing multiple studies regarding the natural history of persistent patent arterial duct, Campbell has surmised that the percentage of patent arterial ducts closing after one year of age is 0.6% per year [7]. Campbell [7] also reviewed the per annum mortality of a patient with a patent arterial duct. This increases with advancing age, from 0.49% per year for subjects aged 2–19 years up to 1.8% per year for patients ages 20 and above, and 30% of these patients die from congestive heart failure. During the preantibiotic era the average age of death in those patients with a patent arterial duct surviving infancy was 36 years, and infective endocarditis was the most common cause of death, accounting for 45% of the deaths [13]. The risk of bacterial endocarditis in the antibiotic era is clearly much lower than the historical studies mentioned. In a retrospective review of patient records at Great Ormond Street Hospital, London from 1984 to 1996 [14], only two cases of endocarditis associated with a patent arterial duct were found among 17,887 cardiac admissions. Total deaths in Sweden between 1960 and 1993 were nearly 3 million, of which only 2 were attributed to infective endocarditis as a complication of patent arterial duct [15]. In the current era, the risk of developing congestive heart failure and/or pulmonary hypertension with a moderate or large duct along with the (low) risk of bacterial endocarditis for even a small duct are indications for intervention in nearly all patients with an isolated (clinically audible) patent arterial duct. The management of the “silent” patent arterial duct detected only by echocardiogram remains controversial. Houston and colleagues [16] defined the “silent” duct as a “clinically undetectable duct identified only by the characteristic color doppler signal,” and estimated the incidence of “silent” duct to be 0.5% of the population. Balzer and coworkers [17] reported a 19‐year‐old male who had subacute bacterial endocarditis (SBE) secondary to a “silent” duct who recovered with antibiotic therapy, followed 8 weeks later with ductal ligation. Given this single case report versus the number of patients predicted to have a “silent” duct, we and others do not routinely recommend closure in these “silent duct” patients unless they have had an episode of SBE [18]. Symptoms and physical findings depend on the size of the duct as well as the pulmonary vascular resistance and associated intracardiac defects. With a small duct, the degree of left‐to‐right shunting is restricted by the narrow lumen and the child may be asymptomatic. The diagnosis is often made at the time of a child’s preschool physical examination, with a typical continuous “machinery” murmur heard in the left second intercostal space. With a moderate‐sized patent arterial duct, the shunt increases significantly over the first few months of life as the pulmonary vascular resistance falls. These children tend to have failure to thrive, recurrent upper respiratory tract infections, and fatigue with exertion. The pulse may be bounding along with an overactive cardiac impulse and continuous murmur. With a large patent arterial duct, an infant develops heart failure in the first weeks of life with tachypnea, tachycardia, and poor feeding. Physical findings include an overactive precordium, wide pulse pressure, and an enlarged liver. Preterm infants with a large duct will frequently have respiratory distress and require intubation and ventilation. Abnormalities on the chest x‐ray are proportional to the degree of left‐to‐right shunting: a large duct results in enlargement of the left atrium and left ventricle, increased pulmonary vascular markings, and interstitial pulmonary edema. Electrocardiographic changes indicative of left ventricular hypertrophy and left atrial enlargement are present. Transthoracic echocardiography, the diagnostic method of choice, can accurately identify the duct anatomy and characterize shunt flow. A left atrium‐to‐aortic diameter ratio of greater than 1.2 : 1 is present in the majority of premature infants with a significant patent arterial duct [19]. Most infants and children with “classic” physical findings and an echocardiogram indicating isolated patent arterial duct will be referred for transcatheter closure. If the echocardiogram findings suggest severe pulmonary hypertension, preintervention cardiac catheterization physiologic assessment should be performed. If elevated pulmonary artery pressures are encountered at the time of the catheterization, oxygen and pulmonary vasodilators are administered to determine the reactivity of the pulmonary bed. Patients with fixed pulmonary hypertension will have systemic desaturation and can exhibit differential cyanosis, with pink face and right hand, and cyanosis of the feet. Patients with fixed elevated pulmonary vascular resistance are not candidates for duct closure because of the high risk of right ventricular failure, and may be considered candidates for lung transplantation and simultaneous patent arterial duct closure [20]. There are many different treatment strategies available for the premature neonate with a patent arterial duct. These include pharmacologic therapy for premature infants (indomethacin), closure in the catheterization lab (coils, occluder devices), video‐assisted thoracoscopic clip closure, and open thoracotomy with ligation or division and oversewing. Management of these patients remains controversial among neonatologists and cardiologists. Indomethacin (an inhibitor of cyclooxygenase and thus prostaglandin synthetase) has been applied clinically since 1976 to constrict the duct and facilitate closure in premature infants [21]. In full‐term infants, indomethacin therapy is rarely successful. A schedule of three doses of 0.1–0.2 mg/kg administered intravenously every 12–24 hours has been widely used. The efficacy of indomethacin compared with simple medical therapy for a patent arterial duct (ventilator support, fluid restriction, and diuretics) in premature infants is well documented. Indocin and ibuprofen, both nonspecific COX inhibitors, have an estimated closure rate of 50–65% in extremely low birth weight infants, but with vasoconstrictive properties there is also a risk of renal injury and intestinal perforation [22, 23]. Some preterm infants, however, may have contraindications to indomethacin therapy, including hyperbilirubinemia, sepsis, coagulation deficiencies, and renal insufficiency. Indomethacin therapy may impair renal function and has been reported to cause gastrointestinal perforation. More recently paracetamol (acetaminophen) has gained popularity as an alternative agent with similar closure rates but fewer reported side effects [24, 25]. Prophylactic treatment of patent arterial ducts in preterm babies is controversial. Prophylactic indomethacin treatment does accelerate ductal closure and reduce the development of bronchopulmonary disease and intraventricular hemorrhage. However, neurodevelopmental outcomes do not appear to be affected. Therefore, some advocate prophylactic patent arterial duct treatment in all extremely premature infants with a moderate to large patent arterial duct [26], while others advocate conservative management in selected patients [27]. If medical therapy is contraindicated or if closure is not obtained following three courses of indomethacin, conversion to a surgical or transcatheter closure strategy is indicated. In the current era, however, fewer and fewer babies are referred from the neonatal intensive care unit for ductal closure via catheter or surgery [28, 29]. Ongoing randomized controlled studies will determine if early patent arterial duct closure has a meaningful impact on outcomes in this high‐risk patient population. Previously the only US Food and Drug Administration (FDA)‐approved device for percutaneous patent arterial duct closure carried an indication for use limited to patients at least 6 months of age and greater than 6 kg weight. For many years off‐label device closure has been performed in premature infants, but as of January 2019 the FDA approved the first device specifically designed for patent arterial duct intervention in this population. The Amplatzer Piccolo™ Occluder (Abbott Laboratories, Abbott Park, IL, USA) was approved in January 2019 for patent arterial duct closure in neonates weighing 700 g or more (Figure 11.3) [30]. Delivery is performed using a 4F catheter in the common femoral vein only, with aortic arch and pulmonary artery imaging performed by transthoracic ultrasound, thus avoiding the need for placement of a high‐risk sheath in the femoral artery [31]. These advancements in technique and miniaturization of equipment represent the current frontier of interventional cardiology, and now allow us to consider a minimally invasive approach to patent arterial duct closure in even the most clinically fragile patients [32, 33].
CHAPTER 11
Patent Arterial Duct
Anatomy and Pathophysiology
Natural History
Clinical Features and Diagnosis
Treatment – Premature Infants
Medical
Transcatheter
Surgical
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