In this chapter, we consider abnormalities of the pulmonary veins, in particular their anomalous connections to the systemic venous system. The variant of partially anomalous pulmonary venous connection associated with the sinus venosus interatrial communication is described in detail in the chapter that follows. The anomalous pulmonary venous connections so commonly associated with isomerism of the atrial appendages are mentioned in this chapter, but have been discussed more fully in Chapter 22 , not least because of the particular problems of nomenclature that arise in the setting of isomerism. Though division of the morphologically left atrium was, in the past, 1 considered a pulmonary venous anomaly, we deal with this lesion, along with division of the morphologically right atrium, in Chapter 26 .
TOTALLY ANOMALOUS PULMONARY VENOUS CONNECTION
Incidence and Aetiology
It was at the turn of the 17th century that Wilson 2 described a ‘monstrous formation of the heart in which the superior caval vein was joined by a trunk formed by two large veins coming out of the lungs’. We now know that the various forms of such totally anomalous pulmonary venous connection, in the absence of isomerism of the atrial appendages, or visceral heterotaxy, accounted for one-fortieth of the patients registered in the New England Regional Infant Cardiac Program. 3 As such, the entity ranked 12th in frequency, and occurred once in 17,000 live births. In the Baltimore–Washington Infant Study, the malformation was encountered less commonly, accounting for 1.5% of all patients with a cardiovascular malformation, and being seen once in 14,700 live births. 4 Totally anomalous pulmonary venous connection is known to be part of the Holt-Oram, Klippel-Feil, phocomelia, and Schachermann syndromes. 5 It is more difficult to establish the incidence of partially anomalous pulmonary venous connection, since anomalous connection of a solitary vein ( Fig. 24-1 ) may be unrecognised either in life or death. Such anomalies have been reported in about 1 in 200 routine postmortems. 6,7 Furthermore, in an extensive investigation based on surgical and autopsy experience, seven-tenths of all cases of anomalous pulmonary venous connection were found to be of the partial variety, albeit that this review included patients with isomerism of the atrial appendages. 8
Earlier reports on totally anomalous pulmonary venous connection stressed the preponderance of males in the setting of infradiaphragmatic drainage, 5 with an equal mix of gender in the remaining types. In those recorded in the New England Regional Infant Cardiac Program, 3 however, two-thirds with supracardiac and cardiac connections were males, while it was the infradiaphragmatic variant that showed an equal mix of genders. As with so many lesions, there are some examples of familial clustering, 9 with one report 10 suggesting autosomal dominant inheritance. Some evidence suggesting maternal exposure during the first 3 months of pregnancy to teratogens emerged from the Baltimore–Washington Infant Study. 4 Reanalysis of that dataset in 2004 11 found the association with maternal exposures inconclusive, but identified a link between totally anomalous connection and paternal exposure to lead prior to conception.
Anatomy
Anomalous pulmonary connections take various forms, and show several important clinical features. The first important feature is the proportion of the pulmonary venous drainage that is connected to sites other than the morphologically left atrium. This can be a solitary pulmonary vein, all of the veins from one lung, or the entirety of the pulmonary venous drainage ( Fig. 24-2 ). Combinations are also possible when all veins do not drain anomalously, so although rare, it can be possible for all of the drainage from one lung, and a solitary vein from the other lung, to be connected to sites other than the morphologically left atrium. Once it has been established that a pulmonary vein, or pulmonary veins, are draining anomalously, it is equally important to determine the site of drainage, and whether all the veins drain to the same site. It is then necessary to seek stenotic areas or regions along the route of anomalous drainage. It is also necessary to establish whether the anomalous pulmonary venous connection is an isolated malformation, or part of a more complex anomaly, and whether there are associated structural malformations of the pulmonary vasculature.
Before discussing these important anatomic variables in more detail, we need to explain our use of the term anomalous pulmonary venous connection. This is because, in certain circumstances, pulmonary veins connected in normal fashion to the morphologically left atrium can drain anomalously to a systemic site, as for example when there is mitral atresia and an atrial septal defect, or fenestration to the coronary sinus, or in presence of the so-called laevoatrial cardinal vein ( Fig. 24-3 ).
A pulmonary vein is connected anomalously only when it is attached to a site other than the morphologically left atrium. In this respect, it is also important to distinguish between the left-sided and the morphologically left atrium. In the presence of isomerism of the right atrial appendages, as we will show, all four pulmonary veins are frequently connected to the roof of an atrium with a morphologically right appendage, which can be left-sided. Because, in this setting, the atrium possesses a morphologically right appendage, this anatomical pattern is anomalous. Indeed, the pulmonary veins must be connected anomalously in the setting of right isomerism irrespective of their site of drainage. The topic of pulmonary venous connections in hearts with isometric appendages, therefore, represents a special situation. It is discussed in depth in Chapter 22 . In this section, we are concerned primarily with totally anomalous connection in the setting of lateralised atrial chambers, in other words the usual and mirror-imaged arrangements, but we will make reference where appropriate to hearts with isomeric appendages.
When all the pulmonary veins are connected anomalously, then usually they drain to the same site. In some situations, nonetheless, different pulmonary veins are connected to separate anomalous sites. This is called mixed drainage. The sites of such drainage are the same as when the entirety of the pulmonary venous return reaches an extracardiac site through a confluence. These sites of anomalous connection are divided into supracardiac, cardiac, and infracardiac groups. The first two, taken together, constitute supradiaphragmatic drainage, while infracardiac drainage is at the same time infradiaphragmatic ( Fig. 24-4 ).
Cardiac and intracardiac anomalous connections account for approximately one-quarter each of the total group. Supracardiac connection can be to the left brachiocephalic vein, directly to the right superior caval vein, to the azygos system of veins, or to the left superior caval vein, albeit that when the left vein drains to the coronary sinus this is considered cardiac drainage. In the most common pattern, the four pulmonary veins usually join in turn to a venous channel behind the left atrium. This channel is traditionally termed the confluence but the individual veins usually join the channel sequentially. From this horizontal channel, a vertical vein typically runs through the left paravertebral gutter to join the left brachiocephalic vein, which then terminates in the right superior caval vein ( Fig. 24-5 ). It is the course of the vertical vein that usually determines whether or not the pathway is obstructed. If the vein passes anterior to the left pulmonary artery, then this course is not associated with obstruction. Should the vein pass between the left pulmonary artery and the left bronchus, these two structures clasp the channel in the so-called bronchopulmonary vice ( Fig. 24-6 ). Obstruction with this snowman pattern of anomalous connection can also occur, albeit rarely, at the opening of the brachiocephalic vein into the superior caval vein. Supracardiac connection can also be found when the vertical vein joins directly with the right superior caval vein. Obstruction may then occur either at this caval venous junction, or in another vice, this time between the right pulmonary artery and the carina. When the anomalous pulmonary veins join the systemic venous system through the azygos vein, the horizontal vein usually crosses from left to right beneath the heart, again receiving the individual pulmonary veins in sequential fashion. The vertical vein then ascends in the right paravertebral gutter, joining the superior caval vein through the azygos vein ( Fig. 24-7 ).
When there is usual, or mirror-imaged, atrial arrangement, then almost always the cardiac form of anomalous connection is found when the pulmonary veins join the right atrium via the coronary sinus ( Fig. 24-8 ). It can be questioned whether this should be considered a cardiac connection, or one via the persistent left superior caval vein. Irrespective of such niceties, there is no question but that the site of return is within the heart, so cardiac connection is an apt description. The individual pulmonary veins can drain in various patterns to the coronary sinus, but the final common pathway is the sinus within the left atrioventricular groove, this typically being enlarged relative to the normal situation. Separate walls of coronary sinus and left atrium then separate the horizontal venous channel from the left atrial cavity, albeit that the walls can readily be removed surgically. Repair of the anomalous connection is then achieved simply by closing both the mouth of the coronary sinus and the interatrial communication, 12 taking care, of course, to respect the atrioventricular conduction tissues within the triangle of Koch. Obstruction is rare when the pulmonary veins drain through the coronary sinus, but can be produced by persistence of the Thebesian valve, or within the sinus when the individual veins connect in unusual fashion.
Direct connection of the pulmonary veins to the morphologically right atrium is exceedingly rare other than in the setting of isomerism of the right atrial appendages. In this setting, the coronary sinus is absent, and most usually the atrial septum is deficient, frequently virtually absent. The pulmonary veins then tend to crowd together, opening through a midline fibrous confluence in the atrial roof ( Fig. 24-9 ). Because the confluence lacks muscle, 13 it can be obstructive. Less frequently in hearts with isomeric right appendages, the atrial septum can be much better formed, yet still the pulmonary veins connect directly to one of the atriums ( Fig. 24-10 ). This arrangement must be anticipated in hearts with usual or mirror-imaged atrial arrangement, but we have yet to identify such a case.
The final site of anomalous connection is both infracardiac and infradiaphragmatic. In this pattern, the pulmonary veins join together, entering a descending vertical vein that passes into the abdomen through the oesophageal orifice of the diaphragm. It then usually drains to the portal vein, or to one of its tributaries ( Fig. 24-11 ). Drainage to the inferior caval vein is very rare. When the infracardiac connection is to the portal venous system, obstruction is almost always present subsequent to closure of the venous duct. Once this component of the fetal circulation has closed, the blood must pass through the hepatic tissues to reach the systemic veins. Additional discrete stenosis can be found as the vertical vein passes through the diaphragm, while the channel can also break up into a delta of smaller channels that terminate in the tributaries of the portal vein.
In all the situations illustrated thus, we have shown the anomalously connecting pulmonary veins draining to the same site within the systemic system. As discussed, it is also possible for different veins to terminate in different anomalous sites. This is called mixed anomalous connection. 14 When seen, some of the veins can join together before draining to one of the multiple sites of anomalous connection, but different parts of the lung usually drain through discrete channels. In very rare situations, all of the pulmonary veins can join a common confluence, but the confluence itself then drains via separate channels, for example to both a left vertical vein and the coronary sinus. 14 With all these patterns of mixed anomalous connection, the same potentials exist for the pathways to become obstructed as when all the pulmonary veins drain anomalously to the same site, as discussed above.
Even excluding those cases of totally anomalous pulmonary venous connection associated with isomeric right atrial appendages, a large proportion of the patients have significant associated malformations. In these patients, such as those with abnormal ventriculo-arterial connections or tetralogy of Fallot, the associated abnormality is probably the major lesion. Even when the anomalous connection is isolated, there is almost always an interatrial communication present, so that venous blood is able to reach the left side of the heart. The atrial septum, nonetheless, can be intact. This then requires an alternative route for blood to reach the left side of the heart.
In any patient with totally anomalous pulmonary venous connection, the size of the left atrium and left ventricle are of obvious concern to the surgeon. At first sight, these structures seem small to the morphologist because of the disparate hyperplasia of the right atrium and right ventricle. Measurements, however, show that the left-sided structures are usually of adequate dimensions. 15 It is rare for there to be any great distance between the pulmonary venous confluence and the left atrium (see Fig. 24-11 ). Taken together, these features serve to facilitate surgical repair in virtually all patients. Problems, when they exist, are likely to be found in patients with mixed drainage, or in the setting of isomerism of the morphologically right atrial appendages.
Further problems can be created by changes in the pulmonary vasculature. Autopsy studies reveal changes in the veins of all patients studied, even including those dying on the first day of age, indicating that the changes themselves occur during fetal life. The veins take on arterial characteristics, while there is also an increase with age in the muscularity of the pulmonary arteries. 15–17 All these features point to the need for immediate surgical repair once the anomaly is diagnosed.
Morphogenesis
Knowledge of development of the pulmonary veins provides a good explanation for anomalous pulmonary venous connections. The developing atrium is itself initially connected to the mediastinum through the so-called dorsal mesocardium, even prior to formation of the lung buds from the trachea (see Chapter 3 ). As the lungs develop, the plexus of intrapulmonary veins joins with a pulmonary venous channel that canalises in the developing mediastinum. The newly formed primary pulmonary vein then uses the original connections of the dorsal mesocardium to gain access with the atrial component of the developing heart tube. 18,19 After normal fusion with the developing intrapulmonary venous plexuses, the pulmonary veins themselves are cannibalised by the atrium to form the venous components of the normal morphologically left atrium. 19 This occurs relatively late in development. Totally anomalous pulmonary venous connection is the consequence of failure of canalisation of the pulmonary venous channel in the mediastinum. Initially, since the lung buds themselves are derived from the foregut, the intrapulmonary veins also have connections to the systemic venous system. 20 Should the pulmonary venous channel fail to develop, these anastomoses between pulmonary and systemic venous systems persist and enlarge. An anastomosis with the anterior cardinal systemic venous system then results in supracardiac anomalous connection. Anastomosis with the systemic venous sinus, or the left sinus horn, produces cardiac connection, while infradiaphragmatic connection is the consequence of anastomosis with the omphalomesenteric system. In the strictest sense, these anastomoses are neither anomalous nor pulmonary. 21 If they persist, nonetheless, they certainly result in an anomalous pulmonary venous connection. Rarely, hearts may be found in which the pulmonary venous channel has formed, but has become atretic in its course between the atrium and the intrapulmonary venous plexuses. 22 Indeed, sometimes the pulmonary veins may be adjacent to the left atrium, but with musculature present between the two developmental components. An anomalous channel, analogous to the laevoatrial cardinal vein, then provides the only route for drainage of pulmonary venous blood. All of these examples, nonetheless, are readily explained using the developmental hypothesis discussed above. It should be noted that while the development of normal pulmonary venous anatomy is well studied, current thoughts about the development of anomalous pulmonary venous connections is conjectural, based on a combination of morphological observations and findings from normal development. The above discussion should, therefore, be viewed in light of that caveat.
Pathophysiology
Shunts
There is an obligatory left-to-right shunt, since pulmonary venous return is to the systemic veins or right atrium. A systemic output can only be maintained if there is a right-to-left shunt, which is almost always at atrial level. As discussed above, exceptional cases have been described in which the atrial septum was intact. In these patients, the right-to-left shunt occurred either at ventricular 21,23 or ductal level. 24
When the right-to-left shunt is at atrial level, there is a tendency for fetal patterns of flow to be maintained by the valvar mechanism of the oval foramen. 5,25 Thus, in most patients with infradiaphragmatic connection, the oxygenated blood ascending the inferior caval vein towards the right atrium is directed towards the left atrium. Systemic arterial oxygen saturation is accordingly higher than that in the pulmonary arteries. When the anomalous venous connection is supracardiac, oxygenated blood tends to be directed down the superior caval vein and through the tricuspid valve. Consequently, in some of these patients, pulmonary arterial blood is more oxygenated than systemic arterial blood. In the others, mixing is complete. Similar patterns are found for anomalous connection to the coronary sinus. This is presumably because the orifice of the coronary sinus is directed more towards the tricuspid valve than the oval fossa. 5,26
Obstruction to Pulmonary Venous Return
Obstruction to pulmonary venous return can occur at any of the anatomical sites documented above. Infants with evidence for borderline venous obstruction should be reevaluated, since the combination of decreasing pulmonary vascular resistance and increased flow of blood to the lungs typically seen in the postnatal period may unmask more severe obstruction. 27 When there is definable obstruction, the right ventricular pressure is usually suprasystemic. 28,29 There are many infants, particularly those with return to the coronary sinus, in whom the systolic pressure in the two ventricles is more or less equal, despite absence of any definable obstruction. 28 Indeed, in one study, no significant difference was found in systolic pressures measured in either the right ventricle or pulmonary arteries between patients with and without obstruction, and with supracardiac or intracardiac connections. 26 This suggests that the main cause of pulmonary hypertension in patients without apparent pulmonary venous obstruction is elevation of pulmonary resistance, presumably as a result of extension of muscle into peripheral arterioles and veins. 15,16 If this is the cause, the almost invariable fall to normal after successful repair indicates that the process is reversible. Alternatively, at least part of the problem may result from undetected anatomical causes of pulmonary venous obstruction. 30
The contribution of the oval foramen to the problem is controversial. In theory, obstruction of this foramen leads to a high right atrial pressure, which impedes pulmonary venous return, thus producing pulmonary hypertension. Gathman and Nadas 5 argued on three grounds, however, that significant obstruction of pulmonary venous return at atrial level was rare. First, patients as a group had similar right atrial pressures whether they were pulmonary hypertensive or not. Second, about a third of patients with pulmonary hypertension had no pressure gradient at atrial level. Indeed, in a few, mean left atrial pressure was higher than right. Third, almost all patients with pulmonary vascular obstruction also had pulmonary venous obstruction. While these arguments are persuasive as to the insignificant role of the oval foramen in producing pulmonary hypertension, they do not rule out the possibility that a small foramen could limit systemic flow.
Consequences of Pulmonary Venous Obstruction
When pulmonary venous return is unobstructed, right ventricular diastolic pressure is low and right ventricular compliance relatively high. Blood returning to the right atrium, therefore, tends to enter the right ventricle rather than the left atrium. Flow of blood to the lungs tends greatly to exceed flow in the systemic circuit. Right ventricular end-diastolic and stroke volumes are considerably increased in consequence. 31,32 Since mixing of pulmonary and systemic venous blood is complete, apart from the minor degrees of streaming discussed above, right atrial and, therefore, systemic arterial blood is well oxygenated, with saturations of oxygen found in excess of 90%.
In the presence of pulmonary venous obstruction, in contrast, pulmonary venous pressure is raised. Pulmonary oedema is then produced if the pressure is sufficiently severe, though bronchopulmonary venous anastomoses may relieve pressure to some degree. In severe cases, nonetheless, pulmonary arterial pressure is raised even above systemic pressure, and pulmonary blood flow is reduced. The right ventricle, therefore, becomes pressure rather than volume overloaded. 31,32 Systemic arterial oxygen saturation may then fall to values of 20% to 30%. The depression of systemic arterial saturation, and possibly also output, results in tissue hypoxemia and metabolic acidosis. These effects of pulmonary venous obstruction are compounded by the changes in small pulmonary veins and arteries already described, which may further increase pulmonary vascular resistance.
In the occasional patient who survives infancy without severe pulmonary venous obstruction, late pulmonary vascular obstructive disease may develop as in those with atrial septal defect. The effects are the same as those of pulmonary venous obstruction, except that no pulmonary oedema occurs.
Presentation and Symptoms
Very occasionally, totally anomalous pulmonary venous connection can present as sudden death in the first 2 months of life. 33 As long ago as 1962, Hastreiter and colleagues 24 recognised that the main determinant of the clinical picture was the presence of pulmonary venous obstruction. Consequently, for each of the ensuing sections relating to the clinical picture, patients will be divided into those with and without pulmonary venous obstruction. Some patients with only modest obstruction fall between the two groups and exhibit features of both.
Patients with severe pulmonary venous obstruction present in the first week or two of life with obvious cyanosis and difficulties with feeding and respiration. 34 In contrast to what is observed in the respiratory distress syndrome, grunting respiration is very rarely seen in obstructed venous return. Pointers to respiratory distress syndrome rather than totally anomalous pulmonary connection are maternal diabetes, prematurity, caesarean section, and very early onset of respiratory difficulties. Any, or all, of these can, nonetheless, be found in the setting of anomalous pulmonary venous connection. In the registry of the Extracorporeal Life Support Society, containing 4823 patients, 623 patients were thought to have persistent fetal circulation. Of these, one-tenth were shown to have congenital heart disease. About half had totally anomalous pulmonary venous connection, while one-tenth had complete transposition. This emphasises how easy it is to mistake totally anomalous pulmonary venous connection for persistent fetal circulation if echocardiography is not performed. 35 A unique mode of presentation, haematemesis, was described in one patient with infradiaphragmatic return to the left gastric vein. 36 Another unique mode was severe unconjugated hyperbilirubinemia in the setting of infradiaphragmatic return. The patient survived exchange transfusion and surgical repair. 37
Patients without severe pulmonary venous obstruction tend to present in heart failure at 2 to 3 months of age. They have a history of difficulties with feeding and, sometimes, chest infections. Cyanosis is generally not a symptom.
Those with severe pulmonary venous obstruction are sick neonates with obvious or severe cyanosis. Skin mottling is frequent, reflecting poor peripheral perfusion and metabolic acidosis. Tachypnea is usually marked, though respiration is quiet. Hepatomegaly is occasionally considerable, particularly when drainage is to the portal vein. The peripheral pulses are often somewhat weak. The precordium is quiet. On auscultation there are usually no murmurs. If a murmur does exist, it is usually unimpressive and mid-systolic. Occasionally a venous hum is heard in the region where pulmonary venous return is obstructed, under the left clavicle, for example, in anomalous connection via a left vertical vein. The first heart sound is single and the second heart sound is described as exhibiting physiological or fixed splitting. 5 The pulmonary component is accentuated and a fourth heart sound may be heard. Rarely, the second heart sound appears single.
When seen from the end of the bed, patients without severe pulmonary venous obstruction resemble patients with large ventricular septal defect. They are scrawny and tachypneic, with retractions. The presence of cyanosis can certainly be missed if the infant is examined in a poor light. Even in a good light, it may not be detected. There is usually hepatomegaly, and rales may well be heard in the lungs.
The peripheral pulses are normal to small and the precordium overactive, but without any thrill. On auscultation, the first heart sound is normal and, usually, there is wide fixed splitting of the second sound. An ejection systolic murmur is heard in the pulmonary area owing to excessive flow through the pulmonary valve. A mid-diastolic murmur tends to be heard at the lower left sternal border, representing excessive flow through the tricuspid valve.
Patients without pulmonary venous obstruction very occasionally survive infancy without heart disease being detected. These patients present as does a typical patient with atrial septal defect, but with the added features of mild cyanosis and clubbing.
Investigations
Chest Radiography
Newborns with severe pulmonary venous obstruction have an extremely characteristic chest radiograph, with a small or normally sized heart framed by ground-glass lung fields 24,38,39 ( Fig. 24-12 ). Kerley B lines are occasionally seen. 40 These appearances are sometimes confused with those of respiratory distress syndrome. The latter diagnosis can easily and correctly be made in most cases in which it is present because of the more patchy distribution of changes in the lung fields. Furthermore, obliteration of part or the entire cardiac silhouette and the appearance of an air bronchogram are both highly characteristic of respiratory distress syndrome and are rare in those patients with totally anomalous pulmonary venous connection.
Patients without severe pulmonary venous obstruction have enlarged hearts because of the right ventricular volume overload, together with engorged lung fields. The pulmonary trunk becomes prominent in older patients, as does the left vertical vein when this is the site of the anomalous venous connection. This gives rise to the snowman appearance, known to almost every paediatrician and also described as the W. C. Fields heart. This is now of mainly historical importance because patients usually have their defect corrected long before the snowman has time to appear, which was usually in the second year of life. 41 Less than one-third of infants with supracardiac anomalous connection exhibit the snowman. 28 Exceptionally, however, the snowman has been seen at 3 months of age. 5
Electrocardiography
The electrocardiogram shows right-axis deviation with a clockwise frontal plane loop and right ventricular hypertrophy. V 1 usually shows an rsR′ pattern, though a qR is seen in four-fifths of patients. The latter might be thought to indicate the presence of more severe pulmonary hypertension, but there is poor correlation between the two. 5 Disturbances of conduction are rare. Under 1 month of age, only about one-twelfth of patients have right atrial hypertrophy, whereas this is seen in three-quarters between 1 and 3 months, and in nine-tenths over 3 months. Patients with pulmonary venous obstruction, who present younger, are much less likely to have right atrial hypertrophy than those without pulmonary venous obstruction.
Echocardiography
Echocardiography is the definitive non-invasive method of diagnosis. Even as long ago as 1979, it was shown that it was possible to image at least one vein connected to the left atrium in 94% of infants under 3 months of age with normally connected pulmonary veins, and at least two in 77%. 42 Correlative anatomical studies suggest that the subcostal and apical approaches image the normal left lower and right upper pulmonary veins, while the suprasternal approach, given a good window, can demonstrate all four. With modern techniques, therefore, it should be possible to demonstrate positively the normal pulmonary venous connections in all neonates and infants. Any infant in whom normal pulmonary venous connections cannot be clearly seen should be sent for further imaging, whether it is additional echocardiography or other modalities.
When performing an echocardiogram, there are certain clues which should direct one towards the diagnosis of totally anomalous pulmonary venous connection. Exclusive right-to-left shunting at the atrial level through an atrial septal defect or patent oval foramen is abnormal in any setting, and should not be presumed to be a result of right ventricular hypertension. It should be assumed that any patient with this finding has totally anomalous pulmonary venous connection until proven otherwise. Other clues include a small left atrium, a dilated superior caval vein ( Fig. 24-13 ), non-pulsatile caudally-directed flow seen below the level of the heart in subcostal imaging, or non-pulsatile cranially-directed flow seen above the level of the heart. Each of these findings should lead one to entertain the possibility of totally anomalous pulmonary venous connection.
Failure to demonstrate any pulmonary vein connected to the left atrium should lead to an assiduous search for the key positive feature required for diagnosis. This is the pulmonary venous confluence, or collecting venous channel, which was recognised in 21 out of 23 patients studied by Smallhorn and colleagues. 43 As has been emphasised, when the pulmonary veins are connected anomalously to the coronary sinus, the collecting venous channel is the coronary sinus itself. From multiple views, the confluence can be seen as an echo-free non-pulsatile region posterior and clearly separate from the left atrium ( Fig. 24-14 ). Care should be taken to distinguish this confluence from a pulmonary artery. The pulmonary arteries originate from the pulmonary trunk, are more anterior, and are usually pulsatile. The subcostal and parasternal short-axis views also demonstrate the size of the interatrial communication. A characteristic picture of the confluence is obtained in the suprasternal or parasternal short-axis views, in which the four converging pulmonary veins can appear in the form of a cross 43 ( Fig. 24-15 ). The vertical vein can be readily identified from the suprasternal approach ( Fig. 24-16 ). The confluence can also be a longer channel, collecting the individual veins sequentially, and, even more rarely, may be somewhat removed from the left atrium. Once the confluence has been discovered, its connection to the systemic venous circulation must be determined.
A descending vein, as found in anomalous infradiaphragmatic connection, can sometimes be seen descending from the confluence from the suprasternal approach. Much more commonly, the descending vein is found by placing the transducer so as to obtain a subcostal long-axis cut of the aorta or inferior caval vein and then scanning from left to right. 43,44 The descending vein is recognised as it penetrates the diaphragm. It is distinguished from the aorta both by its lack of pulsation and its lack of connection to the superior mesenteric artery. It is differentiated from the inferior caval and hepatic veins by its failure to enter one or other atrium and by the fact that it originates behind the heart, where branching can sometimes be recognised ( Fig. 24-17 ). If the site of termination is the portal vein, the descending vein often appears as a finger pointing anteriorly from the oesophageal hiatus towards the hepatic portal. These discriminating features are sufficient in our experience to be diagnostic. If doubt persists, then the inferior caval vein can be distinguished from a descending pulmonary vein by its opacification following injection of microbubbles into a leg vein. 45 Alternatively, pulsed Doppler ultrasound or colour Doppler can be used to show that the descending pulmonary vein contains non-pulsatile blood moving inferiorly, while the inferior caval vein contains blood moving superiorly. 46
A left vertical vein is best seen from the suprasternal approach, in which its connection with the brachiocephalic vein is easily visualised. The vertical vein can usually be traced from the confluence, particularly since its initial upward course and the confluence can often be seen in subcostal and apical cuts ( Fig. 24-18 ). If questions remain, then Doppler interrogation or injection of contrast bubbles into the left arm will demonstrate the direction of flow in the vertical vein. Similar rules apply when the vertical vein ascends in the right paravertrebral gutter and terminates in the azygos vein.
If neither an ascending nor descending vein is identified, then the anomalous connection is most likely either to the coronary sinus or directly to the right atrium. If it is to the coronary sinus, then that structure, best identified in cross-sections in a parasternal long-axis cut or the apical four-chamber cut as it lies within the left atrioventricular groove, will be enlarged and will bulge anterosuperiorly into the left atrium. Great care must be taken to distinguish between enlargement of the coronary sinus owing to persistence of the left superior caval vein and the pattern in which the pulmonary veins drain into it. Colour Doppler can be used to identify pulmonary veins draining into the sinus ( Figs. 24-19 and 24-20 ). The inferior margin of the coronary sinus thus imaged corresponds to the atrioventricular junction. If the superior margin lies more or less parallel to it, this suggests connection to a left superior caval vein. If, however, the superior margin bulges superiorly, then anomalous pulmonary venous connection should be suspected. This distinction can be confirmed by making small tilting and rotational movements of the transducer, which show the anomalously connecting pulmonary veins. Anomalous connection to the right atrium can be diagnosed if there is no ascending or descending vein, the coronary sinus is of normal size and the pulmonary veins can be followed to their site of entry to the right atrium. The echocardiographer should consider measuring the diameter of all four pulmonary veins between hilum and confluence, as the sum of these diameters is a strong and independent predictor of surgical survival. 47 Most of the late deaths in this study were the result of individual pulmonary venous stenosis at sites remote from the surgical anastomosis to the left atrium. In older patients, it can be difficult to image pulmonary veins from the precordium. Under these circumstances, transoesophageal echocardiography can be most helpful. 48
Colour Doppler is essential to diagnosis in these patients. First, it becomes impossible to confuse a left vertical vein draining to the brachiocephalic vein with a persistent left superior caval vein, except in the highly improbable association with atresia of the coronary sinus. The differences demonstrated in direction of flow apply equally to distinction between the inferior caval vein and the descending pulmonary venous pathway. Second, where there is doubt as to whether an image obtained is a genuine pulmonary vein or an artifact, the demonstration of colour within the structure indicates that it is vascular. Third, sites of obstruction along the pulmonary venous pathway can be demonstrated as points of turbulence ( Fig. 24-21 ), or even absent flow, both pre- and post-operatively. 49–51 As is essential with colour Doppler imaging of any venous structure, care must be taken to ensure an appropriate Nyquist limit for optimal detection of pulmonary venous drainage and obstruction.
In areas where colour Doppler suggests obstruction, pulsed wave Doppler offers an objective measure. The presence of a focal increase in flow velocity with a continuous, non-phasic flow pattern distally is a characteristic finding 27 ( Fig. 24-22 ). A sensitivity of 100% and specificity of 85% have been claimed for detection of obstruction by cross-sectional imaging and colour Doppler. 52
It is now standard of care to diagnose and repair totally anomalous pulmonary venous connection based on echocardiography alone. In 1983, Stark and colleagues 53 first reported successful repair of totally anomalous pulmonary venous connection in six young infants without previous cardiac catheterisation. Subsequent experience confirms that skilled use of cross sectional echocardiography avoids the need for cardiac catheterisation in the majority of patients. 54 Mixed totally anomalous pulmonary venous return cannot always be recognised, 54,55 but then such arrangements are not always diagnosed by traditional angiography. As always, if the clinical and cross sectional echocardiographic findings do not fit the clinical situation, additional imaging should be performed without hesitation.
Ultrasound technology has progressed to a degree that it is possible to diagnose totally anomalous pulmonary venous connection by fetal echocardiography, although it is often missed on screening ultrasounds in the absence of additional cardiac anomalies. The presence of a confluence behind the left atrium, a vertical vein, or a widened gap between the descending aorta and the posterior wall of the left atrium are the most consistent echocardiographic clues. 56,57 As with postnatal echocardiography, colour and spectral Doppler analysis can assist greatly in identifying venous obstruction.
Cardiac Catheterisation
Cardiac catheterisation is rarely indicated in this era. If performed, it will document the pathophysiology already indicated. The pulmonary venous anatomy can almost always be delineated non-invasively, and the clinical scenario of pulmonary venous obstruction can almost always be determined without invasive testing. 27,52 If performing catheterisation, it should be remembered that passage of a catheter across an obstruction will temporarily make it worse. Since obtaining the information demands advancing the catheter through an abnormally positioned vein, the safest approach is first to determine the site of the vein. This can be done using echocardiography, computed tomographic angiography, or magnetic resonance imaging. Vertical veins can be entered with ease using a suitably curved catheter. If necessary, a guide wire can be used, passing the catheter from below through the right atrium and via the right superior caval and brachiocephalic veins. 28 When return is to the coronary sinus, this structure may be entered in the usual fashion. Having reached the coronary sinus, it is extremely important to try and enter all pulmonary veins, in order to detect any pressure differences between pulmonary veins or confluence and coronary sinus, or else between coronary sinus and right atrium. It is usually a simple matter to enter the pulmonary confluence when it connects either to the right atrium or to the right superior or inferior caval veins. In the special case of anomalous connection to the portal vein, the umbilical vein is the approach of choice. 58 No-one has reported success in traversing the venous duct from the inferior caval vein. In any case, this structure has often closed by the time the patient is catheterised. The catheter should not be left in position for long, as pulmonary venous pressure can rise as high as 50 mm Hg if it is not removed at once. 59
Traditional Angiography
It is not easy to demonstrate well the detailed anatomy of the route of anomalous return by traditional angiography. This is probably why relatively little was published on the subject. In theory, selective pulmonary venous injection is the method of choice. In practice, it is often a frustrating experience because of the refusal of contrast medium to reflux into pulmonary veins against the current unless there is severe pulmonary venous obstruction. The pulmonary venous injection in obstructed connection to the portal vein published by Tynan and colleagues 58 shows superb opacification of the pulmonary veins. In contrast, on injection into the coronary sinus, it is rare to see opacification of pulmonary veins even if all are connected to it. While the techniques below generally allow one to define the pulmonary venous anatomy, these findings can almost always be defined non-invasively using echocardiography, along with the occasional need for magnetic resonance imaging or computed tomographic imaging as described in the next section.
Pulmonary arteriography works well if there is just the right amount of pulmonary venous obstruction. If this is too severe, and particularly if the duct is patent, it may be impossible to demonstrate the pulmonary veins because of loss of contrast medium into the systemic circulation. This happens despite the use of large doses of rapidly injected contrast medium and filming for 20 seconds or more. Furthermore, in the absence of pulmonary venous obstruction, pulmonary blood supply may be so high that serious dilution of contrast medium prevents optimal visualisation of the pulmonary veins. Mixed anomalous connection may be missed because of inadequate definition and simultaneous opacification of all the cardiac chambers. Selective left or right pulmonary arterial injection may improve recognition of the sites of drainage in mixed return. Pulmonary arterial wedge injection may be even better.
When opacified, the appearance of the vertical vein is characteristic ( Fig. 24-23 ). So is the typical site of obstruction halfway along its course when it is present, representing the site where the vertical vein passes through the vise between the left pulmonary artery and left main bronchus. Anomalous connection to the portal vein is also characteristic. The pulmonary venous confluence, instead of being horizontal, tends to be vertical ( Fig. 24-24 ). This gives the picture poetically termed the tree in winter 60 When the anomalous connection is to the azygos or right superior caval vein, the course of the common pulmonary vein is frequently tortuous. Drainage to the coronary sinus is typified by the golf-ball appearance of the dilated coronary sinus in the frontal projection. 61 Anomalous connection to the right atrium is much more difficult. The angiographic diagnosis depended on the recognition that right atrial opacification preceded that of the left atrium, but for none of the reasons listed above. 61
Computed Tomographic Angiography and Magnetic Resonance Imaging
Technological advances in medical imaging have increased the utilisation of computed tomographic angiography and magnetic resonance imaging in the evaluation of patients with anomalous pulmonary venous connection. 62 Given the inherent complexity involved in understanding the three-dimensional relationships in these patients, multi-planar imaging techniques such as magnetic resonance imaging and computed tomographic angiography allows one to understand the involved anatomy in more straightforward manner. Pulmonary venous connections with a particularly tortuous course, as is often seen with infracardiac connection or drainage via the azygous system, can be difficult to follow by echocardiography. These multi-planar modalities allow one to follow even the most tortuous vessels in a relatively simple fashion. As early as 1991, Masui and colleagues 63 found magnetic resonance imaging to be superior to both echocardiography and conventional angiography in patients with totally anomalous pulmonary venous connection. Since then, numerous other authors have endorsed its utility in these patients. 64–68 Magnetic resonance imaging permits imaging in virtually any plane, allowing for accurate characterisation of the course and size of all pulmonary venous connections, along with other structural anomalies. Contrast-enhanced magnetic resonance angiography allows for three-dimensional reconstructions, which has been proven to be useful in these patients. 69,70 In addition, magnetic resonance imaging allows for functional data including flow quantification and volumetric analysis. However, cardiac magnetic resonance imaging requires a combination of technical expertise and knowledge of cardiac anatomy that is not readily available in all centers, and time-consuming scanning protocols along with the need for transition to equipment suitable for use in magnetic resonance imaging limit the practicality of this imaging modality in the most critically ill infants.
High-resolution computed tomographic angiography using helical multi-detector scanners has proven to be a highly accurate alternative to conventional angiography in the diagnosis and characterisation of anomalous pulmonary venous connections. 71–75 Newer scanners have cut the scanning time to a few seconds, 76 allowing most scans to be performed without sedation. Commercial software is readily available for three-dimensional reconstruction of these datasets, along with datasets from magnetic resonance angiography, permitting those with reasonable knowledge in congenital heart disease to manipulate the anatomy in such a way that is easily understandable. 76,77 In contrast to magnetic resonance angiography, computed tomographic angiography allows for simultaneous three-dimensional reconstructions of additional thoracic structures, making it particularly useful in patients with the bronchopulmonary vise described above. In critically ill patients, computed tomographic angiography can be performed in an expeditious manner with minimal time away from the intensive care unit, without need to transition to specialised equipment. This can be useful for patients who are on extracorporeal membrane oxygenation.
Unlike what is seen with traditional angiography, magnetic resonance angiography and computed tomographic angiography will display contrast in multiple structures simultaneously. This is particularly useful when documenting mixed connections and in understanding spatial relationships in those with more complex anatomic arrangements ( Figs. 24-25 and 24-26 ). Instead of using multiple injections and catheter courses to search for each pulmonary venous connection, all connections can be located on one contrast injection. On the other hand, traditional angiography is likely superior in identifying pulmonary venous drainage from areas of the lung where there is little to no pulmonary blood flow, as these newer modalities have no acceptable substitute for a pulmonary artery wedge angiogram. When imaging patients with suspected supracardiac drainage, it may be useful to inject contrast from below the heart. Assuming the scan is performed with the first pass of contrast through the heart, as is standard procedure, any contrast in a venous structure above the heart can clearly be identified as pulmonary venous in origin ( Fig. 24-27 ). This is particularly useful when trying to differentiate a left superior caval vein from a vertical vein. The converse can be applied to infracardiac connection.
Differential Diagnosis
Much of the basis of differential diagnosis has already been discussed and will not be repeated. As we shall see, pulmonary venous atresia also presents as totally anomalous connection with severe pulmonary venous obstruction. The two conditions, however, may be indistinguishable prior to surgery if no common pulmonary vein is seen by pre-operative imaging.
Unobstructed connection has to be distinguished from other conditions producing heart failure, mild cyanosis, and cardiomegaly with pulmonary plethora and right ventricular hypertrophy. The most important of these is complete transposition with large ventricular septal defect, in which the second heart sound is commonly single. Atrioventricular septal defect with common atrium is easily distinguished by the typical electrocardiogram, showing a superior counter-clockwise frontal plane QRS loop. Totally anomalous connection to the left vertical vein has to be distinguished from the laevoatrial cardinal vein found in association with mitral atresia and intact atrial septum. In both conditions, pulmonary venous blood flow is to a confluence via left vertical vein. In the case of the laevoatrial cardinal vein, the confluence is the left atrium, the pulmonary veins being normally connected.
Course and Prognosis
With medical treatment alone, three-quarters of all children with totally anomalous pulmonary venous connection uncomplicated by isomerism were dead or had undergone surgery by their first birthday. 41 It is of interest that this poor survival occurred despite the fact that less than 10% had infradiaphragmatic anomalous connection. In one study, of 25 patients with pulmonary venous obstruction treated medically, only two survived their first year. 5 In the postmortem study from central Bohemia, which relates to the time before advanced cardiac surgery, 95.8% of deaths occurred in the first year of life. 78 The only place for medical treatment, therefore, is in resuscitation of the critically ill neonate.
In the past, balloon atrial septostomy was shown to produce clinical improvement in the short term in some patients. It was impossible, however, to identify in advance those patients who would benefit from the procedure. 79,80 At the time, septostomy was recommended as a procedure to buy time so as to permit the baby to undergo surgery at a size when the immediate surgical risk was lower. Recent improvements in surgical results, even at very young ages, militate strongly against this expectant policy. Furthermore, balloon atrial septostomy is technically more difficult than in complete transposition because two methods normally used to check that the catheter is in the left atrium do not apply. The left atrial saturation is not higher than the right, and pulmonary veins cannot be entered from the left atrium. Even using biplane screening, it can be difficult to distinguish a catheter positioned in the left atrium from one in a dilated coronary sinus. Sano and colleagues 81 found that in no case did septostomy result in sufficient clinical improvement in critically ill patients to permit deferral of the operation. In patients with severely obstructed pulmonary venous return, stent placement in the area of obstruction can be considered as a temporising measure if surgery cannot be performed in a timely manner. 82,83
Management
Medical Treatment
In the current era, medical management consists solely of supportive measures in preparation for surgical management.
Surgery
With rare exception, neonatal repair is the standard of care. Totally anomalous pulmonary venous connection was the first condition in which the necessity of open heart repair in infancy was forced upon surgeons as a result of the appalling natural history, the lack of any adequate alternative by way of palliation and the potential for excellent long-term results if immediate survival could be achieved. The early results in infancy inevitably involved a high mortality. 28,79,81,84,85 Operations at this time included those in which an anastomosis between the pulmonary venous confluence and the left atrium was created but the interatrial communication was not closed; the common pulmonary vein, if obstructed, was not ligated. 28,81,85 Though subsequent spontaneous closure of the interatrial communication was documented in some patients, 86 this staged approach is now rarely used. Surgical results have now greatly improved ( Table 24-1 ). There used to be debate as to whether age or site of connection was the most important determinant of operative survival, but most recent studies have not shown either to be significant. 87–94 Mortality in current era 10,81,87–91,95,96 has been so low that analysis of risk factors has become challenging. Pre-operative pulmonary venous obstruction has been shown to be a risk factor in some series, 87,88,90,91,96 but this effect may have been neutralised with improved perioperative care. 87,91,92 Another study from Boston Children’s found functionally univentricular physiology, as would be expected, to be a significant risk factor for hospital mortality. 90 In the series reported from the University of Alabama, the significant incremental risk factors for death were younger age, higher New York Heart Association class, higher pulmonary arterial systolic pressure, lower systolic pressure in the left ventricle, and previous balloon atrial septostomy. 97 Bando and colleagues 87 found emergency surgery, diffuse pulmonary vein stenosis, requirement of pre-operative inotropic agents, and post-operative pulmonary hypertensive events to be significant predictors of hospital mortality, while Bogers and colleagues 88 found that the use of circulatory arrest was a risk factor. In a study covering 50 years of surgical results in Toronto, 96 pulmonary venous obstruction, earlier year of repair, younger age at repair, and type of connection were all found to be significant predictors of death. Interestingly, and in contrast to other studies, the cardiac form of connection was associated with an increased risk of surgical mortality. Failure to monitor pulmonary arterial pressure in the post-operative period was put forward as a risk factor for operative death in another series. 98
