Total Anomalous Pulmonary Venous Connection

INTRODUCTION

Background: Total anomalous pulmonary venous connection (TAPVC) consists of an abnormality of blood flow in which all 4 pulmonary veins drain into systemic veins or the right atrium with or without pulmonary venous obstruction. Systemic and pulmonary venous blood mix in the right atrium. An atrial defect or foramen ovale (part of the complex) is important in left ventricular output both in fetal and in newborn circulation.

Embryology

Early in formation of the lungs, the blood coming from the lung buds drains to the splanchnic plexus, which connects to the paired common cardinal and umbilicovitelline veins. The right common cardinal system later evolves into the right sinus venosus, which in turn becomes the right superior vena cava and azygos vein. The left common cardinal vein evolves into the left sinus venosus, which in turn becomes the left superior vena cava and coronary sinus. The umbilicovitelline system becomes the inferior vena cava, ductus venosus, and portal vein.

At 25-27 days’ gestation, the developing pulmonary venous plexus retains connections to the right superior vena cava, left superior vena cava, and portal system. No direct communication to the left atrium exists.

At 27-29 days’ gestation, the primitive pulmonary vein appears as an endothelial out-pouching from either the posterior superior left atrial wall or from the central part of the sinus venosus proximal to the primordial lung venous plexus. Connection between the primitive pulmonary vein and pulmonary venous plexus occurs by 30 days’ gestation. The common pulmonary vein enlarges and incorporates into the left atrium, and, normally, the pulmonary venous part of the splanchnic plexus gradually loses its connection with the cardinal and umbilicovitelline veins.

Knowledge of the normal development of pulmonary venous pathways facilitates understanding of how the various types of anomalous pulmonary venous return might occur. Failure of the common pulmonary vein to connect with the pulmonary venous plexus leads to persistence of one or more earlier venous connections to the right superior vena cava, to the left vertical vein/innominate vein, or to the umbilicovitelline vein/portal vein. Failure of the septum primum to form normally or abnormal septation of the sinus venosus can lead to direct connection of the pulmonary veins to the right atrium. Late obstruction of the common pulmonary vein after earlier venous channels have disappeared can lead to isolated pulmonary vein atresia, a rare and usually fatal condition. Failure of incorporation of the common pulmonary vein may lead to a left atrial shelf or membrane of cor triatriatum (ie, stenosis of the common pulmonary vein).

Since all pulmonary venous return connects to the systemic venous system, right atrial and right ventricular enlargement occurs, and if significant pulmonary venous obstruction develops, right ventricular hypertrophy occurs. TAPVC occurs alone in two thirds of patients and as part of a group of heart defects (eg, heterotaxy syndromes) in approximately one third of patients.

An atrial septal defect or patent foramen ovale, considered part of the complex, serves a vital function in this condition for maintaining left ventricular output. Since diagnosis of most patients occurs in early infancy, a ductus arteriosus frequently is found as well.

Darling proposed the most commonly used classification system for TAPVC based on the site of pulmonary venous drainage. In type I (ie, supracardiac connection), the 4 pulmonary veins drain via a common vein into the right superior vena cava, left superior vena cava, or their tributaries. In type II (ie, cardiac connection), the pulmonary veins connect directly to the right heart (eg, coronary sinus or directly to the right atrium). In type III (ie, infradiaphragmatic connection), the common pulmonary vein travels down anterior to the esophagus through the diaphragm to connect to the portal venous system. In type IV (ie, mixed connections), the right and left pulmonary veins drain to different sites (eg, left pulmonary veins into the left ventricle vein to the left innominate, right pulmonary veins directly into the right atrium or coronary sinus).

Pulmonary venous obstruction may occur in all types of anomalous connections, and in all cases, clinicians must identify any sites of obstruction and treat the obstruction whenever possible at the time of surgical repair. In supracardiac connections, obstruction may occur at the origin of the ascending (vertical) vein or its attachment to the innominate vein, or the vertical vein may be obstructed as it crosses between the left pulmonary artery and the left bronchus. In cardiac connections, obstruction to pulmonary veins seldom develops but may occur at the junction of the common vein to the coronary sinus.

In infradiaphragmatic connections, severe obstruction almost always inhibits pulmonary venous flow with obstruction of the common pulmonary vein. This obstruction occurs either as it travels through the diaphragm, at its junction with the portal vein system, or as an obstruction of pulmonary venous flow as the ductus venosus closes and pulmonary vein flow is forced to cross the liver portal sinusoid system. Finally, in all types, obstruction may occur because of restrictive atrial septal defect size and because of small left atrial size.

Pathophysiology: As a result of the mixture of pulmonary and systemic venous flow, right atrial and right ventricular volume loading develops in all patients with TAPVC. Whether right heart pressure loading also exists depends primarily on whether restriction to flow occurs at the atrial septum or an obstruction to pulmonary venous flow develops. If the foramen ovale is restrictive, right atrial pressure elevates, and systemic and pulmonary venous congestion both occur. Pulmonary blood flow increases, and pulmonary artery hypertension may occur. The left atrium and left ventricle receive less than the normal flow and pump less than the normal volume, with some decrease in the cardiac index.

Most patients with isolated TAPVC have a patent foramen ovale with some degree of restriction to transatrial flow. If no pulmonary venous obstruction exists, pulmonary blood flow increases (eg, 3-5 times the systemic volume) in early infancy, and arterial oxygen saturation is maintained, usually at 90% or higher. Signs of right heart volume load or right heart failure are evident.

If obstruction of pulmonary venous flow exists, then pulmonary venous congestion occurs with increased pulmonary lymphatic flow and increased flow through available alternate pulmonary venous pathways. Reflex pulmonary arterial vasoconstriction also may occur. Increase in pulmonary vascular resistance leads to decrease in pulmonary blood flow and a lower volume of saturated blood in the venous mixture. Decrease in systemic oxygen saturation along with a decrease in the cardiac index may lead to a severe decrease in oxygen delivery.

Frequency:

In the US: TAPVC occurred in 41 of 2659 cases with cardiovascular abnormalities in the Baltimore Washington Infant Study (1981-1987) or in 1.5% of all patients with cardiovascular malformations. Regional prevalence was 6.8 per 100,000 live births. A total of 68% of these patients were diagnosed as neonates (Correa-Villasenor, 1991).

Mortality/Morbidity: The Baltimore Washington Infant Study compared patients with TAPVC to control subjects with cardiac malformations according to the following parameters (Correa-Villasenor, 1991):

Birth weight was less than 2500 g in 16.2% of patients with TAPVC and 6.9% of the control subjects.

Gestational age was less than 38 weeks in 18.9% of patients with TAPVC and 9.3% of the control subjects.

Intrauterine growth retardation occurred in 26.8% of patients with TAPVC and 5.8% of the control subjects.

Sex: In the Baltimore Washington Infant Study, the male-to-female ratio was 18:23 (Correa-Villasenor, 1991). In other reports, a strong male preponderance of 3:1 was observed in patients with infradiaphragmatic drainage.

CLINICAL

History:

Patients with pulmonary vein obstruction

Pulmonary venous obstruction occurs in virtually all patients with subdiaphragmatic drainage and in approximately 50% of patients with supracardiac drainage. Patients with obstruction develop symptoms early, usually at age 24-36 hours, including tachypnea, tachycardia, and cyanosis. Signs of pulmonary hypertension progress with decreasing pulmonary blood flow and worsening cyanosis. Natural history is that of progressive clinical deterioration and early death in the first week or month of life, depending on the degree of pulmonary venous obstruction.

Physical examination findings include severe cyanosis with significant respiratory distress. Cardiac impulse is prominent anteriorly, but, usually, the heart is not enlarged clinically. The pulmonary component of the second heart sound is increased, and a gallop may be present. A murmur usually is not present, yet a systolic murmur over the pulmonary area or a tricuspid insufficiency murmur at the mid and lower left sternal border may be observed. Peripheral pulses usually are normal after birth but may decrease as heart failure progresses. Liver enlargement commonly occurs, especially in TAPVC type III, subdiaphragmatic drainage.

Patients without pulmonary venous obstruction

Patients with unobstructed pulmonary venous flow present with symptoms more similar to a very large atrial septal defect. Mild failure to thrive with greater respiratory effort than normal with activity or recurrent respiratory infections may be present. Often, chest radiographs in patients with respiratory infections reveal significant cardiac enlargement.

Physical examination findings suggest right ventricular volume loading with increase in right ventricular impulse, a wide split-second sound, usually with normal-intensity pulmonary closure, and pulmonary outflow murmur with or without a tricuspid diastolic murmur. Cyanosis infrequently occurs in the first year of life. If a restriction develops in the foramen ovale, some degree of pulmonary hypertension more likely exists, with earlier onset of tachypnea, louder pulmonary closure sound, more prominent right ventricular impulse, and a greater likelihood of systemic and pulmonary venous congestion.

Causes: Sociodemographic findings in patients with TAPVC were similar to those in control subjects. Family history showed no other family members with TAPVC. Noncardiac malformations were present in 9 patients (22%); however, other cardiac and noncardiac malformations were present in 6 first-degree relatives and 7 second-degree relatives of patients with isolated cases (41%). Altogether, a genetic etiology was suspected to contribute to a "failure of targeted pulmonary vein growth" because of the number of multiplex families. In addition, TAPVC has been reported in siblings in other series.

Exposure histories showed possible association of TAPVC with lead or pesticide exposure and raised questions of familial susceptibility to certain environmental teratogens.

TAPVC frequently occurs in association with asplenia and pulmonary atresia. Overall, one third of patients with TAPVC have a major associated cardiovascular malformation and two thirds of patients have isolated TAPVC.

DIFFERENTIALS

Atrial Septal Defect, General Concepts
Hypoplastic Left Heart Syndrome
Mitral Stenosis, Acquired
Mitral Stenosis, Congenital
Mucopolysaccharidosis Type I H/S
Single Ventricle
Transposition of the Great Arteries
Truncus Arteriosus
Ventricular Septal Defect, General Concepts

Other Problems to be Considered:

Newborns

Tachypnea
Cyanosis
Signs of pulmonary venous congestion
Cor triatriatum
Mitral stenosis
Hypoplastic left heart syndrome
Coarctation or interrupted aortic arch
Transposition of the great vessels
Persistent fetal circulation

Infants (usually >6 wk)

Right ventricular volume load and pulmonary hypertension may indicate any of several heart defects, including the following:

Large ventricular septal defect
Common arteriovenous canal
Truncus arteriosus
Single ventricle

Children older than 1 year

Large atrial septal defect
Common atrium partial anomalous pulmonary venous connection

WORKUP

Lab Studies:

Assess and improve (as possible) the oxygenation, acid base status, and hemogram status in these newborns or young infants in preparation for surgery.

Imaging Studies:

Chest radiography

In patients with TAPVC with pulmonary venous obstruction, chest radiographs reveal a normal heart size with a diffuse reticular pattern fanning out from the hilum.

When the pulmonary veins are unobstructed, the heart is enlarged (right atrial and right ventricular enlargement), and pulmonary markings show active increase in size of the pulmonary hilar and midzone vessels.

Echocardiography

Echocardiographic findings, which usually are definitive, have been vital in pinpointing the exact cardiac defect. Hyaline membrane disease may demonstrate similar findings initially. In this setting, electrocardiography helps identify right ventricular hypertrophy in patients with TAPVC, especially in premature babies, and particularly since premature babies usually have a greater level of left ventricular force.

Echocardiography of the precordium in patients with TAPVC depicts right ventricular and pulmonary artery volume loading with flattened or paradoxic septal motion on M-mode imaging. Apical and subcostal 4-chamber views usually best identify individual pulmonary veins and their confluence in patients with TAPVC. Then using multiple views, the common pulmonary vein usually can be tracked to its point of entry to the systemic venous system or to the coronary sinus.

Subcostal long- and short-axis views also can help evaluate size and flow patterns across the foramen ovale.

TAPVC may be difficult to diagnose, especially in an ill newborn on a ventilator, if views of the atrial septum are difficult to obtain or if the common pulmonary vein is small or at an obtuse angle to the left atrial back wall. The addition of color Doppler ultrasonography greatly aids in the diagnosis of individual pulmonary veins and in analysis of the abnormal flow pattern across the atrial septal defect.

Color-flow mapping may be helpful in finding individual pulmonary veins and confirming whether they enter the left atrium. Color-flow ultrasonography may also be used to assess directional flow at the foramen ovale. In patients with TAPVC, flow across the atrial septum predominantly occurs from the right to left.

Altogether, echocardiography with additional color Doppler can help make the diagnosis in the vast majority of patients with TAPVC. In patients with pulmonary inflow obstruction, further diagnostic studies may be needed.

MRI serves to confirm the diagnosis in patients with TAPVC (especially in those with associated lung disease).

Selective pulmonary vein or pulmonary artery angiography may precisely depict a vessel’s anatomy.

Other Tests:

Electrocardiography reveals significant right ventricular hypertrophy in most of these patients, usually with a qR pattern in the right chest leads by age 5-7 days. Right atrial enlargement rarely occurs in these younger patients.

Procedures:

In some patients with multiple sites of pulmonary venous connection, cardiac catheterization serves to better define sites of pulmonary venous obstruction, when other associated cardiac defects are present (ie, pulmonary atresia), and to directly measure foramen ovale size when surgery is delayed.

TREATMENT

Medical Care: No catheter-corrective treatment exists for TAPVC, although atrial septostomy is used in some patients when the foramen ovale is restricted and corrective surgery is delayed for some reason.

Surgical repair is used as treatment for TAPVC whenever it best serves the individual patient. Stabilize the patient prior to surgery as much as possible from a cardiovascular and metabolic standpoint. In a newborn with obstructive TAPVC, stabilization often involves mechanical ventilation, correction of acidosis, inotropic support, and administration of prostaglandin E₁ for patency of patent ductus arteriosus and, in patients with TAPVC type III, for patency of the ductus venous. Nitric oxide may be useful as a pulmonary dilator preoperatively and postoperatively, although care must be used in patients with a small left atrium. Reports indicate that magnesium sulfate is a useful pulmonary vasodilator in these patients. Extracorporeal membrane oxygenation (ECMO) may be life saving in some patients.

Surgical Care: The goal of surgery is to redirect pulmonary vein flow entirely to the left atrium. In patients with a supracardiac or infracardiac connection, the common pulmonary vein is opened wide and connected side to side to the left atrium. The foramen ovale is closed, and the ascending or descending vein is ligated. In a cardiac connection (to right atrium or coronary sinus), the atrial septum is resected partially and a new septum is created surgically, directing pulmonary veins to the left atrium. A coronary sinus may be separately tunneled to the right atrium or left to drain with the pulmonary veins to the left atrium.

MEDICATION

Newborns or patients in early infancy with obstructed TAPVC frequently have pulmonary edema with varying degrees of increase in pulmonary arterial and venous resistance. Pulmonary edema probably is treated best with surgical relief of the pulmonary venous obstruction, but diuretics and assisted ventilation with high fraction of inspired oxygen (FIO₂) and end-expiratory pressure often are helpful preoperatively and postoperatively.

Drug Category: Pulmonary vasodilators -- When sustained severe cyanosis or severe hypercyanotic episodes occur in patients with obstructed TAPVC, treatment with one or more pulmonary vasodilators may be helpful both preoperatively and postoperatively to increase pulmonary blood flow and decrease right-to-left shunting at the atrial septal defect and ductus arteriosus. Vasodilators that are specific and completely pulmonary vascular in action are rare (oxygen may be the most specific at present). The following 3 vasodilators can be used to treat elevated pulmonary vascular resistance in these patients.

Drug Name
Nitric oxide, inhaled (INOmax) -- Stimulates guanylate cyclase to form cyclic GMP, which causes relaxation of vascular smooth muscle.
Since it can be delivered by inhalation directly to alveolar units and is inactivated rapidly by hemoglobin, it is the most selective of currently available pulmonary vascular dilators (except for oxygen). Requires an inhalation delivery system (not available everywhere); approved for use in children in December 1999.
Pediatric Dose Initial dose 80 ppm inhaled with high FIO₂; taper to 20 ppm as safer long-term dose; effect of pulmonary vasodilatation may still be observed at 5 ppm
Delivery system must measure NO concentrations in breathing gas (concentration must be constant throughout respiratory cycle) and must not generate excessive inhaled NO₂
Contraindications Documented hypersensitivity; neonates with dependent right-to-left shunting of blood; methemoglobin-reductase deficiency
Interactions NO donor compounds (eg, nitroprusside, nitroglycerin) may increase risk of developing methemoglobinemia
Pregnancy C - Safety for use during pregnancy has not been established.
Precautions Possible withdrawal problems with prolonged therapy; when weaning, may use type V phosphodiesterase inhibitor to increase cyclic GMP levels to decrease rebound pulmonary hypertension; in patients with small left atria or poorly compliant left ventricles, initial improvement in pulmonary flow can occur, then pulmonary hypertension can return with worsened clinical state; prolonged treatment can cause elevation in methemoglobin levels, which can be measured; caution in thrombocytopenia, anemia, leukopenia, or bleeding disorders

Drug Name
Magnesium sulfate -- Reportedly useful in patients with obstructed TAPVC who have hypercyanotic episodes to decrease pulmonary vascular resistance and decrease pulmonary vascular reactivity. Mechanism of action is believed to be direct action on vascular muscle cells but may also increase formation or release of NO. MgSO₄ has systemic and pulmonary vascular dilating effects, and use of a slow infusion of lower-dose MgSO₄ is wise to avoid systemic hypotension.
Pediatric Dose 20 mg/kg/h IV initially; can gradually increase to 50 mg/kg/h IV over 10-12 h; not to exceed 50 mg/kg/h IV
Contraindications Documented hypersensitivity; preexisting systemic hypotension or hypermagnesemia; heart block, myocardial damage, or severe hepatitis
Interactions Concurrent use with nifedipine may cause hypotension and neuromuscular blockade; may increase neuromuscular blockade seen with aminoglycosides and potentiate neuromuscular blockade produced by tubocurarine, vecuronium, and succinylcholine; may increase CNS effects, toxicity of CNS depressants and betamethasone, and cardiotoxicity of ritodrine
Pregnancy A - Safe in pregnancy
Precautions Magnesium may alter cardiac conduction, leading to heart block in patients taking digitalis; BP, blood gases, respiratory rate, deep tendon reflex, and renal function should be monitored when administered parenterally

Drug Name
Alprostadil (Prostin VR) -- Prostaglandin E₁ (PGE₁) that causes dilation of vascular smooth muscle in the ductus arteriosus, systemic arteries, and pulmonary vascular muscles. In obstructed TAPVC, PGE₁ usually is used as a pulmonary vascular dilator, but its effects on the ductus arteriosus and ductus venosus can be very important (eg, in subdiaphragmatic connection, PGE₁ can help dilate the ductus venosus and improve pulmonary venous flow. In other types of connection with obstruction, PGE₁ can dilate pulmonary arteries and increase pulmonary flow or dilate the ductus arteriosus and systemic arteries and increase right-to-left shunting and worsen cyanosis). PGE₁ is readily available and easily administered, preferably via a large vessel. Care must be take to observe its effects in the complex circulation of TAPVC.
Each 1-mL ampule contains 500 mcg/mL.
Pediatric Dose Initial dose: 0.03-0.1 mcg/kg/min IV; not to exceed 0.2 mcg/kg/min IV
Usual effective maintenance dose can be lower at 0.01-0.05 mcg/kg/min IV
Contraindications Documented hypersensitivity; hyaline membrane disease or respiratory distress syndrome; systemic hypotension may be relative contraindication
Interactions Limited data exist; caution with concurrent use of antiplatelet drugs or anticoagulants
Pregnancy X - Contraindicated in pregnancy
Precautions Most worrisome adverse effect is apnea, which occurs at higher doses (ie, >0.05 mcg/kg/min); adverse effects and toxicity include seizures, fever, hypotension, flushing, leukocytosis, fever, bradycardia, diarrhea, and pulmonary overcirculation; neonates may be intubated prophylactically because of potential risk of apnea (10-12%); prolonged use occasionally is necessary and may be associated with third spacing of fluid; monitor blood oxygenation and arterial pressures

FOLLOW-UP

Complications:

Unfortunately, pulmonary venous obstruction occurs in 5-10% of patients and usually is evident in the first 6 months following surgery. Most commonly, this obstruction is intimal fibrotic hyperplasia of individual pulmonary veins near their junction with the common pulmonary vein. Unfortunately, this form of obstruction is difficult to treat, using either catheter dilation or surgery. Less commonly, obstruction develops at the original anastomotic site and is more easily treated surgically.

Prognosis:

Early surgical results have shown steady improvement over the past 30 years. In patients who underwent surgery before 1970, repair of TAPVC carried a mortality rate higher than 50%. From 1970-1980, centers reported lower mortality rates of 10-20%. Most recent reports indicate an early mortality rate of less than 10%.

Most patients survive surgery without late problem manifestations.

MISCELLANEOUS

Medical/Legal Pitfalls:

TAPVC may be difficult to diagnose, especially in ill newborns on ventilation, if views of the atrial septum are difficult to obtain or if the common pulmonary vein is small or at an obtuse angle to the left atrial back wall. The addition of color Doppler imaging greatly aids in diagnosis in individual pulmonary veins and in analysis of the abnormal flow pattern across the atrial septal defect.

Usually, the need for surgery in these patients is not debatable, although timing can be an issue.

The risk of recurrent pulmonary vein stenosis or anastomosis at the anastomosis site between the common pulmonary vein and the left atrium must be explained to families.

PICTURES

Caption: Picture 1. Types of total anomalous pulmonary venous connection.

Picture Type: Image