OVERVIEW: What every practitioner needs to know

Are you sure your patient has total anomalous pulmonary venous return? What are the typical findings for this disease?

  • Central cyanosis

  • Tachypnea

  • Tachycardia

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What other disease/condition shares some of these symptoms?

  • Partial anomalous pulmonary venous return

  • Atrial septal defect

  • Mitral stenosis

  • Cor triatriatum

  • Persistent fetal circulation

What caused this disease to develop at this time?

This is a type of embryologic defect, in which all 4 pulmonary veins drain into the systemic veins or right atrium, rather than the left atrium. The abnormal venous connection may or may not be obstructed at the point of entry. This disease is present at birth. It typically manifests during early infancy due to excessive pulmonary blood flow with signs of right heart volume overload (no pulmonary venous obstruction), or with central cyanosis if obstruction to pulmonary venous flow is present.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

Arterial oxygen saturation. Infants may be mildly desaturated from an obligate right-to-left shunt at the atrial level, or severely cyanotic with pulmonary venous obstruction.

Hyperoxia test. This is a screening diagnostic test used to differentiate between cardiac and pulmonary causes for central cyanosis (or desaturation). Place infant in room air and get ABG. Place infant on 100% oxygen and repeat ABG. A PaO2 less than 150 mmHg (or increase less than 100 mmHg) on 100% oxygen suggests a cardiac lesion; a PaO2 greater than 200 mmHg (or increase greater than 150 mmHg) on 100% oxygen makes congenital heart disease very unlikely.

Would imaging studies be helpful? If so, which ones?

Chest radiogram. May show a small cardiac silhouette with evidence of pulmonary venous congestion (particularly with pulmonary venous obstruction), or right atrial and right ventricular dilation with excessive pulmonary blood flow and a mildly enlarged cardiac silhouette (with no pulmonary venous obstruction).

Echocardiogram. Often confirms the diagnosis by demonstrating a pulmonary venous confluence posterior to the left atrium with no direct connection to the heart. Echocardiography also delineates the anatomy of the anomalous pulmonary venous connection (supracardiac, cardiac, infracardiac, or mixed), and documents pulmonary venous obstruction, if present. Finally, echocardiography is able to diagnose additional cardiovascular malformations that may occur in up to one-third of patients with total anomalous pulmonary venous connection.

Cardiac catheterization with angiography or cardiac MRI. Demonstrates the pulmonary venous anatomy and areas of stenosis or obstruction. Often necessary to delineate the anatomy with mixed-type anomalous venous return.

Confirming the diagnosis

The clinical decision algorithm includes a high suspicion for total anomalous pulmonary venous return in any neonate with tachypnea, tachycardia, cyanosis, and a normal cardiac silhouette on chest x-ray with or without evidence for pulmonary venous congestion. Initial management willl depend on whether or not there is evidence for pulmonary venous obstruction.

If you are able to confirm that the patient has total anomalous pulmonary venous return, what treatment should be initiated?

Pulmonary venous obstruction occurs in virtually all patients with infracardiac (or subdiaphragmatic) total anomalous pulmonary venous return, and in approximately 50% of patients with supracardiac anomalous veins. Symptoms and signs of obstruction (tachypnea, tachycardia, profound cyanosis) usually occur early in the first 24-48 hours of life, and may progress to cardiovascular collapse and death.

Obstructed total anomalous pulmonary venous return is a surgical emergency that requires re-anastomosis of the pulmonary venous confluence to the left atrium and closure of the atrial septal defect/patent foramen ovale. Stabilizing the patient prior to surgery is important and may include mechanical ventilation, correction of acidosis and anemia, inotropic support and possibly extracorporeal membrane oxygenation. Prostaglandin E1 to maintain patency of the ductus arteriosus should in general be avoided, as this therapy may promote right to left shunting at the ductal level (due to reflex pulmonary arteriolar vasoconstriction with elevated pulmonary vascular resistance), worsening arterial hypoxemia and systemic oxygen delivery.

In the absence of pulmonary venous obstruction, total anomalous pulmonary venous return will present with signs and symptoms similar to a large atrial septal defect with a dilated right atrium and ventricle, tachypnea and increased respiratory effort with activity, and/or recurrent respiratory infections. Initial treatment may include diuretics for symptomatic relief, but ultimately elective surgical correction is generally indicated in the first few months of life.

What are the adverse effects associated with each treatment option?

Treatment for total anomalous pulmonary venous return typically involves surgery to re-anastomose the pulmonary venous confluence to the left atrium and close the atrial septal defect/patent foramen ovale. Postoperative complications include episodic pulmonary hypertension that negatively impacts cardiac output and may require inhaled nitric oxide as a pulmonary vasodilator, or extracorporeal membrane oxygenation.

What are the possible outcomes of total anomalous pulmonary venous return?

Patients with pulmonary venous obstruction at presentation are more prone to recurrent pulmonary venous obstruction, pulmonary hypertension, and progression of irreversible pulmonary vascular disease due to intrinsically abnormal stenotic or hypoplastic pulmonary veins. This relatively infrequent complication is typically fatal with no good treatment options (similar to children with congenital pulmonary vein stenosis). Recently, sutureless pericardial marsupialization has been shown to be associated with satisfactory midterm results in some children.

In the majority of patients, surgical correction is curative, with no further evidence for pulmonary hypertension or recurrent pulmonary venous obstruction. Some patients may develop recurrent obstruction at the surgical anastomosis between the confluence and the left atrium (approximately 10%-20% in most series), and these patients may require re-operation to address these discrete narrowings. Surgical mortality for isolated total anomalous pulmonary venous return is approximately 5%-10%. Mortality in infants with total anomalous pulmonary venous return associated with complex congenital heart disease approaches 50%.

Without surgical intervention, total anomalous pulmonary venous return leads to pulmonary hypertension, right heart failure and greater than 78% mortality in the first year. The risks of surgical intervention primarily relate to the risks of cardiopulmonary bypass, arrhythmias, residual pulmonary venous obstruction, and pulmonary hypertension.

What causes this disease and how frequent is it?

Total anomalous pulmonary venous return is a rare congenital anomaly, occurring in only 1%-3% of children born with cardiovascular malformations. This lesion develops early in gestation, and there is no known cause.

Nearly 70% of patients with total anomalous pulmonary venous return will be diagnosed as neonates. In the Baltimore-Washington Infant Study, birth weight was less than 2500 g, gestational age was less than 38 weeks, and intrauterine growth retardation occurred 2-3 times more frequently in children with total anomalous pulmonary venous return compared with control subjects with other cardiac malformations.

There are no known predisposing environmental exposures, although there is a possible association with lead or pesticide exposure.

The genetics of abnormal cardiovascular development are incompletely understood, although a genetic etiology is suspected due to familial clustering in some series. Gene expression studies in mouse and chick embryos for the platelet-derived growth factor receptor and its ligand show a consistent role in pulmonary vein development, and loss of growth factor receptor function in both organisms causes total anomalous pulmonary venous return similar to humans.

How do these pathogens/genes/exposures cause the disease?

  • Not known.

Other clinical manifestations that might help with diagnosis and management

Reverse differential cyanosis with lower oxygen saturation in the right hand than in the feet has been reported in supracardiac total anomalous pulmonary venous return. The highly saturated superior vena caval blood flow streams preferentially from the right ventricle across the ductus arteriosus to the descending aorta, and the desaturated inferior vena caval flow crosses the foramen ovale into the left ventricle and ascending aorta.

What complications might you expect from the disease or treatment of the disease?

In the case of obstructed total anomalous pulmonary venous return, pulmonary venous congestion leads to reflex pulmonary arteriolar vasoconstriction, decreased pulmonary blood flow, decreased systemic oxygen saturation, and severely decreased systemic oxygen delivery. If profound, this may progress to cardiovascular collapse and death. In addition, a small percentage of infants with surgically repaired total anomalous pulmonary venous return have intrinsically abnormal pulmonary veins that lead to recurrent, progressive pulmonary venous obstruction, systemic or suprasystemic right ventricular pressures, and right heart failure.

Are additional laboratory studies available; even some that are not widely available?

How can total anomalous pulmonary venous return be prevented?

This is an early embryological defect during cardiac development with no known etiological risk factors. This disease cannot be prevented.

What is the evidence?

Seale, AN, Uemura, H, Webber, SA. “Total anomalous pulmonary venous connection: morphology and outcome from an international population-based study”. Circulation. vol. 122. 2010. pp. 2718-26. (This retrospective population-based study of 422 infants born with total anomalous pulmonary venous return in the United Kingdom, Sweden and Ireland described the incidence, clinical presentation, morphology (including associated congenital heart disease, pulmonary venous anatomy, degree of obstruction), surgical outcomes, and overall survival. Risk factors for death after surgical repair by both univariable and multivariable analysis included preoperative pulmonary venous obstruction, associated cardiac lesions requiring staged intervention, postoperative pulmonary hypertension, and age at surgery.)

Kelle, AM, Backer, CL, Gossett, JG. “Total anomalous pulmonary venous connection: results of surgical repair of 100 patients at a single institution”. J Thorac Cardiovasc Surg. vol. 139. 2010. pp. 1387-94. (This retrospective single-institution study of 100 patients undergoing surgical repair of total anomalous pulmonary venous connection identified functional single ventricle anatomy and/or heterotaxy syndrome as risk factors for operative and late mortality and an increased risk for reoperation from anastomotic stricture and pulmonary vein stenosis. On the basis of the morphology of the anomalous pulmonary venous connection in this series, the mortality was highest for those patients with a mixed-type connection [hazard ratio = 3.95; p = .0077]).

Correa-Villaseñor, A, Ferencz, C, Boughman, JA, Neill, CA. “Total anomalous pulmonary venous return: familial and environmental factors. The Baltimore-Washington Infant Study Group”. Teratology. vol. 44. 1991. pp. 415-28. (This report of 41 infants with total anomalous pulmonary venous return ascertained from the Baltimore-Washington Infant Study, a population-based case-control study of cardiovascular malformations, described the prevalence, clinical findings, sociodemographic characteristics, family history, genetic factors, and environmental factors associated with development of total anomalous pulmonary venous return. The results suggest an association of total anomalous pulmonary venous return with family history and genetic disorders, and possibly with environmental exposures [particularly pesticide exposure]).

Devaney, EJ, Chang, AC, Ohye, RG, Bove, EL. “Management of congenital and acquired pulmonary vein stenosis”. Ann Thorac Surg. vol. 81. 2006. pp. 992-5. (This single-center retrospective study of 36 patients undergoing repair of pulmonary vein stenosis (14 with congenital pulmonary vein stenosis, and 22 with acquired pulmonary vein stenosis after repair of total anomalous pulmonary venous return) described overall mortality and risk factors for poor outcome, including associated heart defects, the nonmarsupialization procedure, and bilateral diffuse disease. Sutureless pericardial marsupialization was associated with satisfactory midterm results and appeared superior to other conventional techniques.)

Ongoing controversies regarding etiology, diagnosis, treatment

The etiology is incompletely understood, and there are many theories. Diagnosis and treatment are reasonably incontrovertible. There are a few experimental approaches to recurrent pulmonary venous obstruction, including pulmonary vein stent placement and various anti-inflammatory or antiproliferative medications. None of these approaches has shown significant improvement in medium- or long-term outcomes.