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Common Left-to-Right, Shunts, Dale A. Burkett,, , MD, , KEYWORDS,
Atrial septal defect (ASD)
Ventricular septal defect (VSD),
Patent ductus arteriosus (PDA)
Shunt
Left-to-right shunt, KEY POINTS,
Blood flows to the path of least resistance. The resistance downstream from a shunt varies, based on the location of a shunt.,
Atrial septal defects are communications between the atria, volume load the right heart,, and are generally asymptomatic in infants and young children.,
Ventricular septal defects are communications between the ventricles, volume load the, left heart, and may require intervention early in life.,
A patent ductus arteriosus is a communication between the aorta and pulmonary arteries,, volume loads the left heart, and may require intervention in the neonatal period.,
Medical management of left-to-right shunts often involves diuretics to reduce symptoms, associated with excessive pulmonary blood flow. Transcatheter or surgical intervention, may be necessary., , Video content accompanies this article at http://www.pediatric.theclinics.com., , Congenital heart disease is often made up of communications between the left and, right side of the heart, or the aortic and pulmonary artery, which allow oxygenated, blood to shunt into chambers or vessels that normally carry deoxygenated blood,, so-called left-to-right shunts. Common shunts include atrial septal defects (ASD),, ventricular septal defects (VSD), and a patent ductus arteriosus (PDA). To best understand the shunt physiology in such lesions, it must be emphasized that blood, always flows to the path of least resistance. The overall resistance that determines, shunting differs based on the location of the shunt, but includes the compliance of, a chamber (the ability to stretch), downstream stenosis (above, below, or at a, valve), and vascular resistance. While the resistance determines the direction of, a shunt, the pressure gradient between 2 chambers determines the velocity of, the shunt., , Division of Pediatric Cardiology, Heart Institute, Children’s Hospital Colorado, University of, Colorado, 13123 East 16th Avenue, Aurora, CO, USA, E-mail address: [email protected], Pediatr Clin N Am 67 (2020) 821–842, https://doi.org/10.1016/j.pcl.2020.06.007, 0031-3955/20/ª 2020 Elsevier Inc. All rights reserved., , pediatric.theclinics.com, , Downloaded for Abhishek Srivastava ([email protected]) at Fortis Escorts Heart Institute and, Research Centre from ClinicalKey.com by Elsevier on December 30, 2021. For personal use, only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

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822, , Burkett, , ATRIAL SEPTAL DEFECTS, , An ASD is a communication between the left and right atria. ASDs comprise about 7%, to 8% of congenital heart defects, although up to 50% of children with congenital, heart disease have an ASD as a component of their cardiac abnormalities, highlighting, how commonly ASDs occur in more complex congenital heart disease.1,2 ASDs are, classified based on their location within the atrial septum and embryologic origin., A basic knowledge of normal atrial septal anatomy is useful to understand ASD, anatomy. Septum primum, the first septum to form, is a thin partition between the, atria. It sits on the left atrial (LA) side of a crescentic, thick muscular invagination between the atria, the septum secundum, which forms on the right atrial (RA) side of the, partition and forms the limbus of the fossa ovalis; septum primum forms the valve of, the fossa ovalis (Fig. 1). Superior and inferior endocardial cushions fuse to form the, atrioventricular portion of the septum at the crux of the heart. As atrial septation occurs, the left horn of the embryologic sinus venosus becomes the coronary sinus of, the heart, draining the venous flow from the heart muscle into the RA., Patent Foramen Ovale, , A patent foramen ovale (PFO) represents a normal interatrial communication, as the, flap between the limbus of the fossa ovalis (septum secundum), and the valve of the, fossa ovalis (septum primum) (Fig. 2, Video 1). In fetal life, the valve is pushed into, the left atrium, with right-to-left atrial shunting allowing oxygenated blood from the, ductus venosus to reach the left heart and thus be pumped out to the ascending aorta, and brain. However, postnatally, as LA pressure exceeds RA pressure, the fossa ovalis (septum primum) is pressed against the limbus (septum secundum). If these 2 tissues are not fused, blood can pass between the 2 flaps, as a PFO, which is present in, nearly all newborns and remains patent in 25% to 30% of adults.3 The volume of blood, that can pass through a PFO is minimal and so there is no hemodynamic compromise:, there is insufficient volume to cause right heart dilation, or a flow murmur across the, , , , Fig. 1. Atrial septal anatomy is formed by the thin septum primum (1 ), which forms the, , valve of the fossa ovalis, and the thicker, crescentic septum secundum (2 ), the anteroinferior, border of which is known as the limbus., Downloaded for Abhishek Srivastava ([email protected]) at Fortis Escorts Heart Institute and, Research Centre from ClinicalKey.com by Elsevier on December 30, 2021. For personal use, only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

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Common Left-to-Right Shunts, , Fig. 2. Patent foramen ovale by transthoracic echocardiography, demonstrating flow (red,, arrowhead) between septum primum and septum secundum. LA, left atrium; RA, right, atrium., , pulmonary valve. Although this is thought to be a normal, benign finding, if the rare, physiologic conditions are met the interatrial communication does allow possible, right-to-left interatrial, thus contributing to paradoxic embolic strokes., Atrial Septal Defect Anatomy, , ASDs represent a pathologic communication between the LA and RA, although not all, communications are truly defects in the septum between the 2 chambers. In fact,, some interatrial communications have an entirely normally formed atrial septum. Potential interatrial communications include (Fig. 3):, 1. Secundum ASD—this defect, which accounts for 70% of ASDs and has a female, predominance (2:1), is typically the result of a defect in the thin septum primum (single or multiple fenestrations) (Fig. 4, Videos 2–6)., 2. Sinus venosus defect—this defect accounts for 5% to 10% of interatrial communications, and results from a deficiency in the sinus venosus septal tissue between, the right pulmonary veins and the superior vena cava (SVC) and RA, most, commonly the right upper pulmonary vein and SVC (superior sinus venosus ASD), (Fig. 5, Video 7). The interatrial communication is through a pulmonary vein orifice, in the LA, allowing LA blood to enter the orifice and drain into the SVC/RA. In addition, pulmonary venous return from the right upper pulmonary vein can directly flow, into the SVC/RA. Sinus venosus defects are also associated with anomalous pulmonary venous connections. Rarely, the right lower or middle pulmonary veins, communicate with the RA (inferior sinus venosus defect)., 3. Primum ASD—this interatrial communication is part of the atrioventricular septal, defect spectrum, when failure of endocardial cushion fusion results in failure of, Downloaded for Abhishek Srivastava ([email protected]) at Fortis Escorts Heart Institute and, Research Centre from ClinicalKey.com by Elsevier on December 30, 2021. For personal use, only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved., , 823

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Common Left-to-Right Shunts, , Fig. 5. Superior sinus venosus atrial septal defect (arrowhead) by transthoracic echocardiography, with flow (red, arrowhead) between left atrium (LA) and right atrium (RA). IVC, inferior vena cava; SVC, superior vena cava., , atrioventricular septation (Figs. 6–8, Videos 8–11). Some forms of atrioventricular, septal defect have only an interatrial shunt, commonly referred to as a “partial”, atrioventricular septal defect., 4. Coronary sinus ASD—this rare defect results from a deficiency in the septum between with coronary sinus and the LA, allowing LA blood to enter the coronary sinus and drain into the RA. This is usually associated with a persistent left SVC., 5. Vestibular ASD—this very rare defect is the result of a deficiency in the atrial septal, component derived from the vestibular spine, a muscularized anteroinferior portion, of the atrial septum., , Fig. 6. Primum atrial septal defect (arrowhead) by transthoracic echocardiography. LA, left, atrium; LV, left ventricle; RA, right atrium; RV, right ventricle., Downloaded for Abhishek Srivastava ([email protected]) at Fortis Escorts Heart Institute and, Research Centre from ClinicalKey.com by Elsevier on December 30, 2021. For personal use, only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved., , 825

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826, , Burkett, , Fig. 7. Primum atrial septal defect (arrowhead) by transesophageal echocardiography,, with flow (blue) from the left (LA) to the right atrium (RA). LV, left ventricle; RV, right, ventricle., , Physiology, , As blood flows to the path of least resistance, interatrial shunting is related to atrial, compliance, which is, in large part, due to ventricular compliance. The LA is typically, less compliant than the right, due to stiffer atrial walls, and the position of the LA between the spine posteriorly and the rest of the heart anteriorly. Importantly, the LA, must overcome left ventricular (LV) diastolic pressure, which is typically higher than, the right ventricle (RV). The RA is typically more compliant than the left, due to more, distensible atrial walls, and the anterior position of the RA with distensible systemic, veins. The RA must overcome RV diastolic pressure, which is typically lower than, the LV. Mitral and tricuspid valve stenosis can also play important roles in the downstream resistance of each atrium., Thus, atrial shunting typically flows from a less compliant LA to the more compliant, RA. There is typically very little pressure gradient between the atria and so the velocity, of the shunt is typically quite low. The shunt results in right heart dilation and increased, pulmonary blood flow., , Fig. 8. Primum atrial septal defect (solid arrowhead) by 3D transesophageal echocardiography, with the defect basal to the atrioventricular valve (open arrowhead). RA, right atrium;, RV, right ventricle., Downloaded for Abhishek Srivastava ([email protected]) at Fortis Escorts Heart Institute and, Research Centre from ClinicalKey.com by Elsevier on December 30, 2021. For personal use, only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

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Common Left-to-Right Shunts, , Clinical Features, , Increased flow across the pulmonary valve results in turbulence, heard as an ejection, murmur, and also delayed closure of the valve, with fixed splitting of S2. A diastolic, inflow murmur may be appreciated at the left lower sternal border., Infants are typically asymptomatic. Even older children with moderate shunts are, asymptomatic, whereas those with a large shunt may have fatigue and dyspnea., Diagnostic Studies, , Radiography may demonstrate cardiomegaly, with engorged pulmonary arteries and, distal vasculature. The electrocardiogram often demonstrates RA enlargement, rsR0 or, RSR0 in V1, and possibly prolonged P-R interval., Echocardiography can visualize the atrial septum, RA and RV dilation, increased, flow across the pulmonary valve, pulmonary veins, and the coronary sinus. Transesophageal echocardiography visualizes the atrial septum and pulmonary veins well,, although it requires general anesthesia. 3D echocardiography can provide detailed images of interatrial shunts, although it may be limited by imaging windows, limitations in, frame rate, or the ability to use an adult-size transesophageal probe., Contrast-enhanced echocardiography, completed with agitated saline, blood, or albumin, may be able to better define certain ASDs, and importantly can demonstrate, right-to-left atrial shunting with visualization of contrast in the left heart., Cardiac catheterization is typically not necessary for diagnosis of an ASD, although, measurement of the effective shunt (pulmonary:systemic blood flow) and identification, of anomalous pulmonary venous drainage are possible. It also affords the ability to, assess for pulmonary hypertension, a dangerous potential sequela of prolonged, increased pulmonary blood flow., Cardiac MRI can potentially identify interatrial communications, and can also quantify the effective shunt. A computed tomography (CT) scan can identify some interatrial, communications, although it involves irradiation and does not quantify the amount of, shunting., Natural History, , ASDs typically have a benign course and are usually asymptomatic in infants and, young children. In fact, some do not present for decades. Exercise intolerance, atrial, tachyarrhythmias, RV dysfunction, and pulmonary hypertension rates increase with, age in those with untreated ASDs. Spontaneous closure or decrease in size of secundum ASDs is common, and more likely if less than 8 mm and younger at the time of, diagnosis.4–7 Spontaneous closure of primum, coronary sinus, and sinus venosus, ASDs are unlikely. Pulmonary vascular disease can occur in 5% to 10% of patients, with untreated ASDs, with a predominance in women and those over 20 years.8, Treatment, , Treatment of secundum ASDs includes both transcatheter and surgical closure,, although there is typically little indication for repair in young children. As ASDs are, not typically symptomatic in young children, and often decrease in size or even close, with increasing age, elective repair is often delayed until at least age 4 to 5 years. In, fact, repair in children less than 15 kg rarely improves somatic growth and is associated with complications.9, Transcatheter device closure of secundum ASDs is common, with numerous, possible devices of various sizes, making closure of a wide range of ASD sizes, possible (Figs. 9 and 10, Videos 12–15). Complication rates are typically quite low,, Downloaded for Abhishek Srivastava ([email protected]) at Fortis Escorts Heart Institute and, Research Centre from ClinicalKey.com by Elsevier on December 30, 2021. For personal use, only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved., , 827

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828, , Burkett, , Fig. 9. Device closure of a secundum atrial septal defect (A) (solid arrowhead) by 3D transesophageal echocardiography, with a device (open arrowhead) deployed across the atrial, septum, viewed from the right atrium (RA) (B), above the atrial septum (C), and from the, left atrium (LA) (D). 2 , septum secundum with limbus (asterisk); 1 , septum primum., , and success rates very high.10 Atrial septal rims do limit the candidacy of some patients for transcatheter closure; such patients require surgical closure, which is effective and has a very low rate of death or significant complications in children, although it, has a higher rate of complications in adults.11 In children, compared with transcatheter, closure, surgical closure is associated with longer length of stay, higher infection rates,, and greater cost.12, Surgical closure is usually required for sinus venosus ASDs, which involves patch, closure and sometimes rerouting of the SVC (Warden procedure). Surgical closure, of coronary sinus ASDs typically involves closure of the coronary sinus ostium, preventing interatrial shunting, but also rerouting of coronary sinus venous return to the, left atrium. Surgical closure is also required for vestibular ASDs and primum ASDs,, often in conjunction with surgical repair of the left atrioventricular valve., VENTRICULAR SEPTAL DEFECTS, , A VSD is a communication in the ventricular septum. Behind the bicuspid aortic valve,, it is the most common form of congenital heart disease. VSDs are present in w0.25%, of all live births, although they are more commonly identified in studies with screening, echocardiography and in premature infants.13,14 They account for 20% of isolated, congenital heart defects.2, Downloaded for Abhishek Srivastava ([email protected]) at Fortis Escorts Heart Institute and, Research Centre from ClinicalKey.com by Elsevier on December 30, 2021. For personal use, only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

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Common Left-to-Right Shunts, , Fig. 10. Device closure of a secundum atrial septal defect (solid arrowhead) by 3D transesophageal echocardiography, as viewed from the right (RA) (A) and left (LA) atrium (B). A device (open arrowhead) is deployed across the atrial septum (C), and then released (D). 2 ,, septum secundum with limbus (asterisk); 1 , septum primum., , Ventricular Septal Defect Anatomy, , There has been significant historical variability in the description and identification of, VSDs, with the same defect having multiple monikers, or a single name applying to a, variety of different lesions.15 However, recent attempts have been made to unify, nomenclature (Fig. 11):16, 1. Perimembranous central VSD—this defect involves the thin membranous ventricular septum, which lies between the aortic and tricuspid valves (Figs. 12–14, Videos, 16–18). Once thought to be the most common VSD, the use of echocardiography, has demonstrated this defect to be less common than muscular defects in neonates, although it is more common in complex congenital heart disease., 2. Inlet VSD without a common atrioventricular junction (not associated with an atrioventricular septal defect)—such defects open into the RV inlet and extend along the, septal leaflet of the tricuspid valve. They can have malalignment between the atrial, and ventricular septae, which can result in straddling and/or override of the, tricuspid valve., 3. Trabecular muscular VSD—these defects are completely bordered by muscle, and, are located within the trabecular muscular septum, in the posterior, mid, anterior or, apical septum (Figs. 15 and 16, Videos 19 and 20). These defects are the most, common VSDs, and the most likely to close spontaneously., Downloaded for Abhishek Srivastava ([email protected]) at Fortis Escorts Heart Institute and, Research Centre from ClinicalKey.com by Elsevier on December 30, 2021. For personal use, only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved., , 829

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830, , Burkett, , Fig. 11. Ventricular septal defect (VSD) anatomy: a perimembranous VSD (1), involving the, membranous septum; an inlet VSD without a common atrioventricular junction (2) in the, inlet portion of the right ventricle (RV); muscular VSDs in the mid (3a), posterior (3b), and, anterior septum (3c), and apical region (3d); outlet VSD (4), cradled between the limbs of, the septomarginal trabeculation (SMB). AAo, ascending aorta; IVC, inferior vena cava;, MPA, main pulmonary artery; RA, right atrium; S, septal leaflet of the tricuspid valve;, SVC, superior vena cava., , 4. Outlet VSD—these defects lie within the limbs of the septal band (septomarginal, trabeculation), just below the RV outlet. They can have no malalignment of the, outlet septum, or malalignment of the outlet septum—either anterior or posterior., Atrioventricular septal defects involve endocardial cushion defects and abnormal, atrioventricular septation, frequently with an interventricular shunt present, which is, often referred to as an “inlet VSD,” although this falls outside of the above nomenclature. With failure of atrioventricular septation, a prominent interventricular shunt may, be present., Physiology, , Blood flows to the path of least resistance. For VSDs, downstream resistance is mostly, due to pulmonary and systemic vascular resistances, but also includes any arterial, stenosis, pulmonary and aortic valve stenosis, and RV and LV outflow tract obstruction. In normal VSD physiology, pulmonary vascular resistance is less than systemic, vascular resistance, and so during systole blood flows from LV through the VSD,, Downloaded for Abhishek Srivastava ([email protected]) at Fortis Escorts Heart Institute and, Research Centre from ClinicalKey.com by Elsevier on December 30, 2021. For personal use, only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

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Common Left-to-Right Shunts, , Fig. 12. Perimembranous ventricular septal defect (arrowhead) by transthoracic echocardiography (parasternal long axis), with a communication and flow (red) between the left, (LV) and right (RV) ventricles., , Fig. 13. Perimembranous ventricular septal defect (arrowhead) by transthoracic echocardiography (parasternal short axis), with a communication and flow (red) between the left, and right (RV) ventricles. LA, left atrium; RA, right atrium., Downloaded for Abhishek Srivastava ([email protected]) at Fortis Escorts Heart Institute and, Research Centre from ClinicalKey.com by Elsevier on December 30, 2021. For personal use, only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved., , 831

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832, , Burkett, , Fig. 14. Perimembranous ventricular septal defect (arrowhead) by transthoracic echocardiography (apical window), with a communication and flow (red) between the left (LV) and, right (RV) ventricles. LA, left atrium., , through the RV, and out into the pulmonary arteries, returning to the left heart. Thus,, VSDs typically lead to left heart dilation. Although resistance determines the direction, of blood flow, the interventricular pressure gradient yields the VSD velocity; if the VSD, is large, there is minimal pressure gradient between the LV and RV, resulting in low velocity shunting., At birth, RV pressures are typically increased in the setting of high pulmonary, vascular resistance, with minimal interventricular pressure gradient and low velocity, , Fig. 15. Small anterior muscular ventricular septal defect by transthoracic echocardiography, (parasternal short axis) with flow (red) through the defect. LV, left ventricle; RV, right, ventricle., Downloaded for Abhishek Srivastava ([email protected]) at Fortis Escorts Heart Institute and, Research Centre from ClinicalKey.com by Elsevier on December 30, 2021. For personal use, only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

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Common Left-to-Right Shunts, , Fig. 16. Small posterior muscular ventricular septal defect by transthoracic echocardiography (parasternal short axis) with flow (red) through the defect. LV, left ventricle; RV, right, ventricle., , VSD flow, which can be difficult to auscultate. Thus, VSDs are commonly not appreciated shortly after birth, but are first heard weeks later, once pulmonary vascular, resistance and RV pressures are decreased., The pressure difference between the LV and RV results in the velocity of the VSD,, using the modified Bernoulli equation (pressure difference 5 4 V2). With this, we can, estimate pulmonary artery systolic pressure. If we know systemic systolic blood pressure, we know the LV systolic pressure (eg, 100 mm Hg), as long as there is no aortic, valve stenosis, which would create a discrepancy between the aortic and LV pressures. Using the modified Bernoulli equation, we can calculate the gradient from the, LV to the RV (eg, 60 mm Hg), and thus know the RV systolic pressure (eg, 40 mm, Hg), which should be similar to the pulmonary artery systolic pressure (in the absence, of pulmonary valve stenosis)., VSD location can play an important role for associated findings. Perimembranous and, outlet VSDs can be associated with aortic valve prolapse and aortic insufficiency. Perimembranous VSDs can also be associated with both subaortic membranes, which can, cause LV outflow tract obstruction and aortic insufficiency, and also a doublechambered RV, where muscle bundles in the RV obstruct outflow. Such findings can, be associated with ejection murmurs through the LV outflow and RV outflow, as well, as a high-pitched diastolic decrescendo murmur if aortic insufficiency is present., Such findings can persist even if the VSD spontaneously regresses or undergoes repair., Clinical Features, , At birth, VSDs are often not appreciated on examination. However, over weeks and, months, as pulmonary vascular resistance drops, a murmur is often appreciated,, with the pitch related to the velocity of the flow through the VSD. As LV pressure, quickly exceeds RV pressure during isovolumic contraction, before the aortic valve, opens, an S1 coincident holosystolic murmur can be present. Muscular VSDs can, squeeze closed during systole as the muscle contracts, resulting in shorter systolic, murmurs. The murmur is often harsh (due to multiple frequencies) and best heard at, the left lower sternal border. Small defects can allow for a larger interventricular pressure difference, and thus a higher velocity VSD shunt and murmur. Larger defects, result in higher RV systolic pressure and thus smaller interventricular pressure gradients, and so shunt murmurs are usually lower pitched., Downloaded for Abhishek Srivastava ([email protected]) at Fortis Escorts Heart Institute and, Research Centre from ClinicalKey.com by Elsevier on December 30, 2021. For personal use, only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved., , 833

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834, , Burkett, , Children with small VSDs are typically asymptomatic. With moderate and larger, VSDs, children can develop tachypnea, increased work of breathing, and sweating,, related to increased sympathetic tone and pulmonary edema. Poor feeding can, develop, as can poor weight gain despite expected caloric intake, consistent with, heart failure in children (caloric intake does not sufficiently meet both the increased, cardiovascular metabolic demands and systemic metabolic demands for somatic, growth)., Diagnostic Studies, , Radiography is normal in children with small VSDs, although cardiomegaly, pulmonary vascular prominence, and pulmonary edema can be present with large lesions., With small VSDs electrocardiography is typically normal, although left axis deviation, LA abnormality, LV hypertrophy, and RV hypertrophy can be seen with larger, lesions., Echocardiography is able to visualize the ventricular septum well by 2D and 3D imaging. Doppler echocardiography determines the direction and velocity of VSD flow,, providing information about RV and pulmonary artery systolic pressures. Echocardiography can also assess associated anomalies, such as aortic valve prolapse, aortic, insufficiency, subaortic membranes, double-chamber RV, and straddling mitral or, tricuspid valves. Transesophageal echocardiography can demonstrate the anatomy, well, perhaps with better visualization than transthoracic echocardiography in older, children and adults. 3D echocardiography can detail VSD size and location, as well, as pertinent surrounding structures, and has been useful for transcatheter device, closure. Cardiac MRI and CT scans can detail VSDs and provide opportunity for 3D, modeling, although they are not typically used in those with adequate echocardiography windows., Cardiac catheterization is not routine for diagnosis of VSDs, but can be useful for, quantifying the magnitude of VSD shunting and cardiac output, evaluating pulmonary, vascular resistance, and assessing associated lesions., Natural History, , Although common at birth, VSD spontaneous closure rate is high, with up to 98% of, VSDs closing spontaneously by 6 years of life, especially muscular VSDs; even perimembranous VSDs are capable of closing, especially those less than 4 mm.17,18, Closure of perimembranous VSDs is usually by aneurysmal tricuspid valve septal, leaflet tissue growing over the defect, and for muscular VSDs is typically hypertrophy, and growth of septal muscle.19, Given this trajectory, avoiding surgical intervention, if possible, is warranted, as, many VSDs decrease in size enough to preclude intervention. Medical management, with diuretics and/or heart failure therapy may allow the VSD time to close., Untreated moderate and larger VSDs can lead to pulmonary hypertension, and, possibly reversal of VSD shunting, with RV-to-LV flow, known as Eisenmenger syndrome. This is associated with cyanosis, polycythemia, iron deficiency, hemoptysis,, embolic events, cranial abscesses, and death., Endocarditis is a recognized potential, though uncommon, complication of untreated VSDs. Although only w2% of adult patients with untreated VSD develop infective endocarditis, this represents an 11- to 30-fold increased risk for endocarditis over, the general population.20 Currently, subacute bacterial endocarditis prophylaxis risk is, not recommended for VSDs, given the substantial number of children with a VSD who, undergo spontaneous closure with very low infective endocarditis risk., Downloaded for Abhishek Srivastava ([email protected]) at Fortis Escorts Heart Institute and, Research Centre from ClinicalKey.com by Elsevier on December 30, 2021. For personal use, only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

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Common Left-to-Right Shunts, , Treatment, , Small VSDs do not typically require treatment, given they cannot allow enough blood, to flow through them to lead to left heart dilation and heart failure. However, even small, VSDs can be complicated by associated defects, such as double-chambered RV,, subaortic membrane or aortic valve prolapse, which are often indications in themselves for surgical repair. If such associated lesions are not found, typically small, VSDs are monitored intermittently for spontaneous closure., For larger VSDs, medical management is often attempted. This includes diuretics to, treat pulmonary edema and heart failure symptoms. In addition, medications such as, digoxin are used, which has been shown to increase ventricular contractility and, improve symptoms.21,22 Medical management can improve symptoms for patients, and may allow enough time for VSDs to decrease in size and hemodynamic effect., However, for large defects, medical management is merely a temporizing therapy, and does not avoid a definitive repair., Surgical closure for larger VSDs is often necessary and this remains the most common pediatric cardiovascular surgical repair, with typically very low mortality, (<<1%).11,23,24 Therefore, attention has been turned to reducing morbidity. Factors, that lead to increased morbidity, such as prolonged intubation, intensive care stay, or, length of admission, include the weight at the time of operation (with smaller infants having a longer length of stay), the presence of a genetic syndrome, and longer cardiopulmonary bypass time.24,25 Surgical options include primary (suture) and patch closure, (Fig. 17). Long-term outcomes after surgery include arrhythmias, LV and RV dysfunction, aortic insufficiency, and decreased exercise capacity; risk factors for late events, include concomitant cardiac lesions and longer aortic cross-clamp times.26, Pulmonary artery banding involves a surgeon placing bands around the pulmonary, arteries, increasing the resistance to pulmonary blood flow, and thus reducing excessive pulmonary blood flow. This technique is used when it is thought that, with time,, VSDs will eventually close, as is the case for multiple small muscular VSDs that result, in a cumulative large interventricular shunt. Once the VSD burden is reduced or, resolved, the bands can be removed., Transcatheter VSD closure has gained popularity in the last 2 decades for closure of, muscular VSDs as well as some perimembranous VSDs (Videos 21–25). Risks include, residual shunts (16%), arrhythmias (10%), valvular defects (4%), and complete heart, block in 1.1%; some studies cite even fewer complications.27,28 Transcatheter device, , Fig. 17. A large anterior malalignment-type ventricular septal defect (solid arrowhead) by, transthoracic echocardiography (apical window), before (A) and after (B) surgical patch, closure (open arrowhead). Ao, aorta; LA, left atrium; LV, left ventricle; RV, right ventricle., Downloaded for Abhishek Srivastava ([email protected]) at Fortis Escorts Heart Institute and, Research Centre from ClinicalKey.com by Elsevier on December 30, 2021. For personal use, only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved., , 835

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836, , Burkett, , closure is not routinely performed for outlet VSDs or atrioventricular septal defect, interventricular communications. Rather, they are typically reserved for muscular, VSDs and perimembranous VSD that have a pocket of tissue that can seat the device, away from the aortic valve., PATENT DUCTUS ARTERIOSUS, , The ductus arteriosus, a normal vessel connecting the pulmonary arteries and aorta in, fetal life, allows blood entering the RV during fetal life to pass into the aorta. In the, fetus, the fluid-filled lungs result in high resistance to flow in the pulmonary arteries,, which receive only 16% of the combined ventricular cardiac output. In contrast, the, ductus arteriosus sees w41% of combined cardiac output.29, Unlike the walls of other blood vessels, which contain elastic fibers in the medial, layer, the ductus arteriosus medial layer contains smooth muscle.30,31 After birth,, the smooth muscle contracts and thickens, and the intimal layer thickens, decreasing, the lumen size and resulting in functional closure of the ductus arteriosus, noted in, 44% of infants at 24 hours, and 88% at 48 hours. It is during this functional closure, that the ductus arteriosus is responsive to therapies to promote patency. Permanent, closure is completed in the following days to weeks. It involves necrosis of the subintimal layer and eventual replacement of the muscular layer with fibrosis, forming the, ligamentum arteriosum., Prostaglandins, produced by cyclooxygenase enzymes, relax the ductus arteriosus, in fetal life, and administration after birth keeps a ductus arteriosus open in certain, forms of congenital heart disease.32–34 Inhibition of cyclooxygenase enzymes reduces, circulating prostaglandin, causing ductus arteriosus constriction both in the fetus and, postnatally.35 At birth, the rise in arterial oxygen tension, and the decrease in circulating prostaglandin levels with removal of the placenta both trigger ductal, constriction., Failure of the ductus arteriosus to close postnatally results in a PDA.31 The incidence, of a PDA at 6 weeks of life among term infants ranges from w3 to 8/10,000 live births,, with a 2:1 female predominance. Prematurity is the most substantial risk factor for a, PDA, with an overall greater than 10-fold increase risk of PDA in premature infants.36,37, The more premature an infant, the greater the risk of a PDA: more than 80% of those, less than 1250 g have a PDA. The rate increases with altitude, with a slight increase in, those greater than 3000 m (9842 feet), and a substantial increase in those above, 4000 m (13,123 feet); infants greater than 4500 m (14,763 feet) have a 30-fold, increased risk of a PDA.38,39, Patent Ductus Arteriosus Anatomy, , Although both right and left PDAs are possible, by far the most common is a left-sided, PDA, between the main pulmonary artery and the proximal descending aorta (Fig. 18,, Videos 26–29). The vessel usually tapers from aortic to pulmonary arterial end. Even, with closure of the PDA, the ductal ampulla is often still present and visible, giving, some clue as to the location of the ductus arteriosus ligament. This can prove helpful, in the evaluation for a vascular ring when the PDA is closed. In premature infants and, those with ductal-dependent cardiovascular lesions, the PDA can be quite large, even, similar in size to the aorta., Physiology, , Pulmonary and systemic vascular resistance are the primary determinants of PDA, shunting; arterial obstruction may also play a role. The length and diameter contribute, Downloaded for Abhishek Srivastava ([email protected]) at Fortis Escorts Heart Institute and, Research Centre from ClinicalKey.com by Elsevier on December 30, 2021. For personal use, only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

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Common Left-to-Right Shunts, , Fig. 18. Small patent ductus arteriosus (solid arrowhead) by transthoracic echocardiography,, with flow (red) through the ductus from the aorta into pulmonary arteries (A). After device, (open arrowhead) closure of the ductus arteriosus (B) there is no residual shunt. LPA, left, pulmonary artery; MPA, main pulmonary artery; RPA, right pulmonary artery., , to the resistance to shunting through a PDA. Immediately after birth, when pulmonary, vascular resistance is still high, flow through a PDA is often bidirectional, with right-toleft flow in systole. As pulmonary vascular resistance drops, the shunt becomes all, left-to-right., Left-to-right shunting through the PDA results in increased pulmonary blood flow, and thus pulmonary venous return to the left heart, and increased flow through the, aortic valve and ascending aorta. A large shunt will thus cause pulmonary edema,, left heart dilation, and increased flow through the mitral and aortic valves. This physiology results in increased sympathetic tone, leading to tachypnea, tachycardia, and, sweating. Although compensatory mechanisms are more fully developed in older children and adults, they are not well developed in newborns, and even less-so in premature infants. Premature infants also have fewer contractile elements within the, myocardium, and lower calcium levels than term infants.40 Thus, premature infants, can develop heart failure earlier than term infants with the same size PDA., The size of the PDA can play a role in pulmonary artery pressures, as a large PDA will, essentially cause equalization of pulmonary and aortic pressures. A small PDA can, provide enough restriction to flow to allow a gradient to form between the 2 vessels., The presence of such a gradient can be helpful when trying to estimate pulmonary artery systolic pressure, as the aortic pressure is obtained from the systemic blood, pressure., Clinical Features, , Clinical features vary based on the size of the PDA shunt. For small PDAs, with less, than 1.5:1 pulmonary:systemic blood flow ratio, there is enough restriction to prevent, any significant amount of increased pulmonary blood flow, and thus left heart dilation., The restriction to flow may allow a pressure gradient between the aorta and pulmonary, artery, which can yield a murmur as turbulent flow enters the pulmonary artery; this will, be continuous (“machine-like”) if the pressure difference between the vessels is always increased, as is seen when pulmonary vascular resistance has dropped. The, respiratory examination is usually normal, and pulses are normal., With a moderate PDA (pulmonary:systemic blood flow ratio of 1.5–2.2:1), the volume load to the left heart is large enough to cause dilation. In addition, pulmonary, edema is common, and may cause respiratory distress in premature infants. A, Downloaded for Abhishek Srivastava ([email protected]) at Fortis Escorts Heart Institute and, Research Centre from ClinicalKey.com by Elsevier on December 30, 2021. For personal use, only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved., , 837

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838, , Burkett, , continuous murmur is often present on auscultation, although as the PDA is larger,, pulmonary pressures are usually higher with a lower interarterial gradient and thus, lower pitched murmur. A flow murmur might also be heard across the aortic valve., With diastolic run-off from the aorta into the PDA, diastolic systemic blood pressure, can be low, with a wide pulse pressure. This pulse pressure is what is palpated, when pulses are felt, and so the palpated pulses are typically increased., Infants with a large PDA (pulmonary:systemic blood flow ratio of >2.2:1) will present, with left heart dilation, pulmonary edema, and heart failure, with poor weight gain, poor, feeding, increased work of breathing, and sweating. Tachycardia and tachypnea are, common, as are rales. Given the large defect, a significant pressure gradient is typically absent, and so a continuous murmur may not be present. However, a flow, murmur is present across the aortic valve, and a diastolic rumble may be present, across the mitral valve. P2 may be loud given increased pulmonary artery pressures., Diastolic blood pressure is lower, and the pulse pressure is wide, resulting in bounding, pulses., Diagnostic Studies, , Radiography is typically normal with a small PDA. However, with moderate and larger, PDAs, there is evidence of left heart dilation and cardiomegaly, as well as increased, pulmonary vascular markings proximally and distally. The electrocardiogram is typically normal in small PDAs, although with moderate and large PDAs, left axis deviation,, LA abnormality, and LV hypertrophy are often present., Echocardiography can visualize the PDA and the shunt direction and velocity using, Doppler imaging. Estimations of the interarterial pressure gradient can be calculated, from the PDA velocity, although long tubular PDAs are a poor use of the Bernoulli, equation., Cardiac catheterization is rarely used for diagnosis of a PDA, although it is regularly, used to close the PDA. In such situations, angiography can detail the duct, and the, surrounding aorta and pulmonary arteries. Assessment of the hemodynamic impact, of the shunt is feasible, as is evaluation for pulmonary hypertension., Cardiac MRI and CT scans are able to demonstrate the PDA well, and can provide, 3D reconstructions of the vessel and surrounding anatomy. Cardiac MRI is also, capable of quantifying the shunt., Natural History, , In the current era, most PDAs are detected in infancy and treated. However, before, widespread diagnosis and treatment, infant mortality, infective endarteritis/endocarditis, heart failure, and pulmonary vascular obstructive disease were frequently encountered, and the mortality rate was as high as 60% by age 60 years, although closure, was documented in a wide range of adults.41 In premature infants with a significant, PDA, mortality may be as high as 20% at 1 year, although this is not attributable, entirely to the PDA alone, and it is difficult to isolate the role of the PDA in the development of intracranial bleeds, necrotizing enterocolitis, sepsis, and respiratory failure.42 Bacterial endocarditis/endarteritis is extremely uncommon in developed, countries, but is associated with PDAs in underdeveloped countries, although the, risk is lower than that for VSDs. Currently, subacute bacterial endocarditis prophylaxis, is not recommended for PDAs., Treatment, , Treatment is recommended for moderate or larger PDAs associated with left heart volume overload or reversible pulmonary hypertension; in those with severe,, Downloaded for Abhishek Srivastava ([email protected]) at Fortis Escorts Heart Institute and, Research Centre from ClinicalKey.com by Elsevier on December 30, 2021. For personal use, only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

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Common Left-to-Right Shunts, , suprasystemic pulmonary hypertension, a PDA may prove advantageous to allow a, “pop-off” for the pulmonary circulation and can help preserve RV function., Therapeutic options for PDA closure include pharmacotherapy, transcatheter, closure, and surgical ligation. As cyclooxygenase produces prostaglandins, which, maintain a PDA, the use of medications that inhibit cyclooxygenase have been successfully used to induce PDA closure. This includes indomethacin and ibuprofen,, though indomethacin is typically ineffective for term infants and older patients. Interestingly, acetaminophen has also proven effective at closure of PDAs.43 In a recent, meta-analysis of the use of indomethacin, ibuprofen, and acetaminophen, highdose oral ibuprofen was shown to have the best odds for closure of hemodynamically, significant PDA in premature infants.44 There have been clinician concerns for necrotizing enterocolitis with the use of oral ibuprofen, although high-dose oral ibuprofen, was actually shown to have the best cumulative probability for preventing necrotizing, enterocolitis, suggesting the risk of necrotizing enterocolitis is likely related to the, presence of the PDA rather than the treatment.44 Interestingly, no statistical difference, in mortality was noted for treatment of PDA versus placebo, suggesting that closure of, a hemodynamically significant PDA may not actually reduce mortality in preterm infants.44 Similarly, others have found that as much as 85% of very-low-birth-weight infants will have spontaneous closure of their PDA.45, Transcatheter closure of PDAs has been gaining popularity in the previous decades, over surgical ligation (see Fig. 18, Video 30). Recent devices can be very successful at, PDA closure, reaching as high as 100% efficacy.46–49 Complications include device, embolization, infection, femoral vessel damage or thrombosis, and vascular or valvar, damage, although rates of complications are low., Surgical ligation was once the predominant method for closure of a PDA. It is typically approached from a lateral thoracotomy, although video-assisted thorascopic, surgery has also been undertaken. Although success rate is high, complication rates, include recurrent laryngeal nerve paralysis, infection, respiratory compromise, scoliosis, pleural effusions, and pneumothorax. Compared with transcatheter closure in, a meta-analysis, surgery was shown to be more successful at PDA closure, and length, of stay was shorter for the transcatheter approach.50 This study did not use the more, recent and successful devices., DISCLOSURE, , The author has no relationships to disclose., SUPPLEMENTARY DATA, , Supplementary data related to this article can be found online at https://doi.org/10., 1016/j.pcl.2020.06.007., REFERENCES, , 1. Hoffman JI, Kaplan S. The incidence of congenital heart disease. J Am Coll Cardiol 2002;39:1890–900., 2. Botto LD, Correa A, Erickson JD. Racial and temporal variations in the prevalence, of heart defects. Pediatrics 2001;107:E32., 3. Hagen PT, Scholz DG, Edwards WD. Incidence and size of patent foramen ovale, during the first 10 decades of life: an autopsy study of 965 normal hearts. Mayo, Clin Proc 1984;59:17–20., Downloaded for Abhishek Srivastava ([email protected]) at Fortis Escorts Heart Institute and, Research Centre from ClinicalKey.com by Elsevier on December 30, 2021. For personal use, only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved., , 839