Part B: Heart

INTRODUCTION

Cyanotic congenital heart defects are the most important group of defects necessitating surgical intervention in the neonatal period. In general, this group of defects is characterized by ductal dependency of pulmonary blood flow (or effective pulmonary blood flow) but with notable exceptions of truncus arteriosus (TrA) and obstructed total anomalous pulmonary venous return or connection (TAPVR).

Cyanotic heart defects should be considered and ruled out or confirmed in any newborn presenting with cyanosis (see Chapter 80 for differential diagnosis of cyanosis in the neonate), although in a cyanotic neonate the response to oxygen, heart murmurs, chest roentgenogram, and electrocardiogram (ECG) can offer clues to cardiac defects and prompt further evaluation. The echocardiogram is the mainstay of diagnosis to delineate the morphology of the heart defect and plan intervention.

In the current era, fetal obstetric ultrasound and fetal echocardiography have enabled us to accurately diagnose congenital heart defects in the majority of neonates before they are born.

This modality has changed the presentation and management of this group of neonates. Because the diagnosis is often established before birth, the emphasis has shifted more on planning the management immediately after birth rather than establishing the diagnosis as in the past. However, a neonatologist still is faced with undiagnosed cyanotic newborns for which all clinical skills can be tested.

Once the diagnosis is confirmed, adequacy of pulmonary blood flow and systemic blood flow should be assessed and pulmonary venous obstruction should be ruled out. Physiology-specific therapeutic medical management should be instituted, and surgical treatment should be planned. In patients with low birth weight or in premature neonates, the approach to “wait and grow the patient” has not been promising. Waiting prior to surgical palliation increases preoperative complications without gaining any benefits.¹ Even in this group of patients, an early correction is indicated, and in patients with functional single ventricles, appropriate early surgical palliation is indicated.

TOTAL ANOMALOUS PULMONARY VENOUS RETURN

Introduction

Total anomalous pulmonary venous return (TAPVR) or connection is a cardiac malformation in which there is no direct connection between any pulmonary vein and the left atrium; rather, all the pulmonary veins connect to the right atrium or one of its tributaries. A patent foramen ovale (PFO) or atrial septal defect (ASD) is present and is necessary for survival after birth in all newborns with TAPVR.²

TAPVR is a rare congenital cardiac anomaly occurring in about 1.5% of children born with congenital heart defects. In addition, it can occur as an associated defect with many other congenital cardiac defects, especially in newborns with heterotaxy syndromes with single functional ventricles. Nevertheless, it is one of the few lesions necessitating urgent or emergent cardiac surgery in the neonatal period.

Morphology

TAPVR morphology (Figure 18-1A) can be categorized into 4 broad anatomic types:

1. The supracardiac type is the most common (45%); here, the pulmonary veins drain via either the ascending vertical vein to the innominate vein or directly to the superior vena cava (SVC) and rarely to the azygos vein. About two-thirds of these have pulmonary venous obstruction, often at the junction of the vertical vein to the systemic vein.

2. In the cardiac type (20%), drainage is directly into the right atrium or into the coronary sinus (CS). Pulmonary venous obstruction is rare but may be seen in up to 20% at the CS ostia or orifices of individual veins or their confluence.

3. In the infracardiac type (25%), drainage occurs via the descending vertical vein into the portal vein or rarely into the inferior vena cava. These are by definition always obstructed to some extent because the pulmonary venous return has to pass through the hepatic capillary system. In addition, they have a high incidence (80% to 90%) of obstruction, often at the junction of the vertical vein to the systemic vein.

4. The mixed type (the least common at 5%–10%) consists of a combination of one or more of the 3 other types described. It can be technically most challenging to repair.

In patients with isolated TAPVR, atrial septal communication, which is essential for survival, and a patent ductus arteriosus (PDA) are the only associated defects. The cardiac chambers and valves are almost always normally formed.

Even the youngest infants dying with the malformation often have structural changes in the lungs. Increased pulmonary arterial (PA) muscularity is seen in all infants dying with TAPVR, as evidenced by arterial wall thickness and vein wall thickness. There is also extension of muscle into smaller and more peripheral arteries than normal.

Clinical Presentation, Pathophysiology, and Diagnosis

Neonates usually present with tachypnea and respiratory distress.³ Cyanosis is prominent when there is pulmonary venous obstruction. In the absence of obstruction, cyanosis is often overshadowed by tachypnea. Right-to-left shunting at the level of the PDA also adds to the cyanosis.

The neonate with obstructed TAPVR often is in critical condition, requiring tracheal intubation and ventilator support. It is not uncommon to see these patients mistakenly diagnosed as having pulmonary pathology such as respiratory distress syndrome, meconium aspiration, bronchiolitis, and so on. TAPVR should always be considered in the differential diagnosis of any neonate presenting with cyanosis or tachypnea.

In TAPVR, the right atrium is the common mixing chamber, which often is reflected in the frequent finding of the close similarity of oxygen content and saturations from the right atrium, left atrium, PA, and systemic artery. However, because of streaming of systemic venous return in the right atrium, directing inferior vena caval blood through the foramen ovale to the mitral valve and SVC blood through the tricuspid valve (TV), there can be considerable variation in different patients. This can be affected further by the size of the atrial communication. The hemodynamics of the nonobstructive types of TAPVR is similar to that of a large ASD. These neonates may present later in the neonatal period as the right ventricular (RV) compliance increases and the pulmonary vascular resistance (PVR) falls, and the ASD may become relatively inadequate in size.

A chest x-ray (Figure 18-1B) of neonates with TAPVR and pulmonary venous obstruction shows diffuse haziness or, in severe forms, a ground-glass appearance. In the supracardiac type, the appearance often is described as a “snowman sign.” These signs are less marked when the pulmonary circuit can decompress via a PDA.

In the current era, even with fetal screening, TAPVR is often undiagnosed unless a fetal cardiac echocardiogram is part of prenatal evaluation. Postnatally, cardiac echo (Figure 18-2) is the definitive means of diagnosis. In some, a cardiac catheterization and angiography or a high-resolution computed tomographic (CT) scan may be needed to define the pulmonary venous anatomy.

Neonates born with TAPVR in general have an unfavorable prognosis. Mortality during the first few weeks or months of life is common in most neonates in whom tachypnea, cyanosis, and clinical evidence of low cardiac output develop, with only about 50% surviving beyond 3 months of life. Such neonates usually have pulmonary venous obstruction, long pulmonary venous pathways, and a small interatrial communication. Only about half the neonates surviving to age 3 months survive to 1 year.

Management

Regarding management,^{4, 5, and 6} surgery should be undertaken emergently, often immediately after diagnosis, in neonates and infants who are critically ill. These are usually neonates with obstructed TAPVR. A brief period of preoperative preparation and stabilization while the diagnosis is being confirmed is all that should be expected. This involves correcting metabolic acidosis and optimizing the ventilation. Prostaglandin E (PGE) is not indicated unless suprasystemic RV pressure is documented by echo. In such instances, right-to-left ductal shunting may improve systemic cardiac output. Rarely, the neonate is so critically ill with significant pulmonary injury that extracorporeal membrane oxygenation (ECMO) may be indicated for a few days prior to surgery. However, in stable neonates, typically without pulmonary venous obstruction, the operation can be scheduled electively.

Surgery is performed on cardiopulmonary bypass with or without circulatory arrest. This commonly involves anastomosing the common pulmonary venous chamber to the back of the left atrium (Figure 18-3). In TAPVR to the CS, the CS is flayed open into the left atrium. If the pulmonary veins are stenotic, each individual vein is flayed open; currently, a suture-less technique is favored in this group. This involves suturing the margins of the cut-open back wall of the left atrium to the pericardium beyond the pulmonary venous openings.

Postoperative management can be challenging in these neonates. They often have high PVR, which will require aggressive treatment of acidosis, hyperventilation, and inhaled nitric oxide. The left ventricle (LV) is also often noncompliant and is sensitive to preload. Monitoring right atrial, left atrial, and PA pressure with indwelling catheters placed during surgery is helpful.

Outcomes

Surgical outcome^{7, 8, and 9} in neonates has steadily improved in the decades since 1970. Data from the database of the Society of Thoracic Surgeons show overall early mortality was 12.0% between 2002 and 2004. For infants falling within the normal weight range, mortality was 9.9%; it was 29.2% for infants less than 2.5 kg body weight.

Recurrent pulmonary venous obstruction is seen in 5% to 10% of neonates and often occurs within a few weeks to months after surgery. While anastomotic stenosis is uncommon and can easily be corrected by reoperation, true pulmonary vein obstruction is often not amenable to surgical or any other form of intervention.

TRANSPOSITION OF GREAT ARTERIES

Introduction

Complete transposition of the great arteries (TGA) is probably the most common cyanotic congenital heart defect in neonates. It accounts for approximately 5% of all congenital heart defects with male preponderance. If untreated (without PGE or balloon septostomy), mortality is high: 30% at 1 week, 50% at 1 month, and 90% at 1 year.

Morphology

Morphologically,^10,11 in TGA, as the name implies, the aorta is transposed to the RV and the PA to the LV. The aorta is anterior and commonly to the right of the PA; therefore, the prefix d is used for dextroposition, which is the most common type of complete transposition (d-TGA). The atria and ventricles are in normal relationship. Although the coronary arteries arise from the aorta, in at least a third the coronary artery origins and course are abnormal. All patients with TGA have an interatrial septal communication (PFO or ASD) and a PDA at birth. In about 70% of patients with d-TGA, the ventricular septum is intact (d-TGA/IVS), and the remaining 30% have a ventricular septal defect (d-TGA/VSD). Pulmonary stenosis, coarctation of the aorta (COA), and aortic arch obstruction are seen in about 25% to 35% of patients with d-TGA/VSD but they are rare in patients with d-TGA/IVS.

Coronary arteries originate from the sinuses of Valsalva facing the PA and are normal in two-thirds of the patients, with the left coronary artery originating from the leftward anterior-facing sinus and the right coronary artery (RCA) from the rightward posterior-facing sinus. In the rest, the pattern of origin and course is abnormal. The most common is the origin of the circumflex coronary artery from the RCA. A single origin of all coronary arteries and an intramural course of the coronary artery within the aortic wall are not infrequent and can pose technical challenges for the surgeon.

Pathophysiology

In d-TGA, the systemic venous blood returning to the RV is ejected back into the systemic bed through the aorta without passing through the lungs, and the pulmonary venous blood returning to the LV is ejected back into the lungs through the PA. This arrangement of 2 parallel circulations does not affect fetal survival because the placenta is the source of oxygenated blood but is incompatible with life in the postnatal period. Hence, after birth survival depends on adequate communication between the 2 parallel circuits at the level of PDA, ASD, and VSD (if present). The extent of mixing is determined by vascular resistance in each of the circulations, size of the communications between the 2 circuits, compliance of the ventricles, and volume of blood flow. Inadequate mixing results in hypoxia, hypercapnia, metabolic acidosis, and eventually death if untreated. Immediate postnatal interventions are primarily designed to maximize mixing of oxygenated and deoxygenated blood.

Clinical Presentation and Diagnosis

Cyanosis is the dominant clinical feature of these neonates, and it is often unresponsive to inhaled oxygen. Cyanosis may be less apparent in neonates with large ASDs and large PDAs, except occasionally because of streaming there is inadequate mixing of oxygenated and deoxygenated blood resulting in intractable cyanosis. In neonates with d-TGA/VSD, cyanosis is less apparent.

At presentation, these neonates often have unstable hemodynamics and a varying degree of acidosis. Physical examination may reveal a mildly hyperactive precordium with prominent single second heart sound and soft systolic murmurs. Peripheral arterial pulses may be prominent if the PDA is large. This may also result in symptoms of congested lungs. Chest x-ray often shows a mildly enlarged heart with a typical appearance (Figure 18-4).

Depending on the institution and country, in the current era prenatal diagnosis of TGA varies from 20% to 75%, and in such instances planned management almost always results in a stable neonate. Echocardiography is the mainstay of diagnosis and most often the only modality of imaging needed (Figure 18-5). Echocardiography can give all the necessary information, including the coronary anatomy needed for surgical planning. Rarely, a CT angiogram or a cardiac catheterization is needed.

Cardiac catheterization is usually a palliative tool in TGA to perform balloon septostomy.

Management

The preoperative management of a neonate with TGA/IVS is directed to increase mixing of oxygenated and deoxygenated blood between the 2 parallel circulations with the goal of increasing systemic oxygen delivery. PGE₂ infusion is started, and if necessary, a balloon atrial septostomy is performed either at the bedside in the neonatal intensive care unit (NICU) under echo guidance or in the cardiac catheterization lab. Most neonates do not require mechanical ventilation.

Some patients may not have adequate mixing of the oxygenated and deoxygenated blood despite these interventions; in such patients, inotropic support to increase the cardiac output and paralyzing the neonate and providing mechanical ventilation to decrease the metabolic needs may be necessary. Rarely, emergent surgery may be needed. In addition to these measures, correcting the metabolic abnormalities may be necessary.

On the other hand, neonates with TGA/VSD generally do not require PGE₂ or balloon septostomy if the VSD is large.

Surgical treatment is undertaken within the first few days of life, and it is not advisable to delay beyond 2 weeks of birth.¹² If there is a large VSD, some surgeons elect to wait for 2 to 4 weeks. The current procedure of choice is the arterial switch operation (ASO; Figure 18-6), which has replaced the atrial switch procedures, such as the Senning and Mustard operations.

The ASO is performed with cardiopulmonary bypass under cardiac arrest with cardioplegia with or without hypothermia. The procedure consists of transferring the aorta and coronary arteries to the LV and the PA with its branches to the RV.

In this procedure, the native pulmonary valve becomes the neoaortic valve and the native aortic valve becomes the neopulmonary valve. In addition, the PAs are translocated anterior to the aorta (Lecompte maneuver). Transferring the coronary arteries, the neoaorta¹³ is the critical step in ASO. The PDA is ligated and divided. The ASD and VSD, if present, are closed.

Associated defects like COA or aortic arch obstruction are also repaired. In patients with LV outflow tract obstruction (LVOTO), an assessment is made whether it is dynamic or if it can be resected. In some patients with TGA/VSD/LVOTO, the pulmonary annulus is hypoplastic, the subpulmonary LV outflow tract (LVOT) is hypoplastic, or both. In such instances, a palliative procedure such as a systemic-to-PA shunt is undertaken; a primary repair is preferred by some surgeons. The operations for this subset of patients are known as the Rastelli procedure, REV procedure, or Bex-Nikkaidoh procedure. In the Rastelli or REV procedures, the LV is baffled to the aorta through the VSD; in the Bex-Nikkaidoh procedure, the aorta along with the valve and coronaries are translocated to the LV.

Outcomes

The early results^{12,14, 15, 16, and 17} for the ASO have significantly improved since the late 1980s. The current survival rate for the ASO in those with TGA with or without VSD is less than 5%. If one excludes the high-risk patients, then the mortality is about 1% or less in most major centers. The risk factors for early death are also variable with experience. However, prematurity, low birth weight, single intramural coronary artery, aortic arch obstruction, multiple VSDs, hypoplasia of the RV, and older neonate/infant with TGA/IVS are some important risk factors. Many of these are neutralized in experienced hands. Preoperative physiologic state is also an important contributor to early death.

Late supravalvar PA stenosis and coronary artery obstruction are uncommon but important complications that require continued follow-up in these infants.

Another rarer complication, neoaortic valve regurgitation, may require even longer follow-up to determine its extent and significance.

TETRALOGY OF FALLOT

Introduction

Tetralogy of Fallot (TOF) is a common cyanotic congenital heart defect and accounts for 10% of all congenital heart defects. In 1888, Fallot described 4 related cardiac abnormalities, which together are known as TOF: VSD; PA stenosis; dextrorotation of the aorta (rightward), which overrides the VSD; and RV hypertrophy. Untreated, about 30% do not survive beyond 3 months, and 10% survive to the age of 21.

Morphology

Morphologically,^18,19 most likely the anterocephalad deviation of the outlet septum and an abnormal relationship of this outlet septum to the rest of the interventricular septum result in all 4 morphologic features. The VSD in TOF is typically conoventricular or perimembranous, but it can also be subarterial with an absent outlet septum. In about 5% of patients, an additional VSD may be present. The crowding of the RV outflow tract (RVOT) causes RV outflow tract obstruction (RVOTO). This results in varying degrees of pulmonary valve abnormality (stenosis, hypoplasia, or atresia) and sometimes supravalvar PA narrowing. The subvalvar infundibulum is narrow and muscle bound in a majority of patients. In a small number of patients, the PAs can be hypoplastic. In the subgroup of patients with pulmonary valve atresia, the PAs are typically duct dependent. In about 25% of these patients, the pulmonary blood flow is derived from aortopulmonary collaterals.

In about 5% of patients with TOF, the coronary artery abnormalities are the most common and are the origin of the left anterior descending (LAD) branch from the RCA.

Clinical Presentation, Pathophysiology, and Diagnosis

Because of RVOTO, the venous blood from the RV is ejected into the aorta through the VSD; this is facilitated to some extent by the overriding of the aorta into the RV. Cyanosis becomes more pronounced as the severity of RVOTO increases. In patients with pulmonary valve atresia, all the venous blood is ejected into the aorta. As the severity of RVOTO increases, so does the dependency of pulmonary blood flow on the presence of a PDA or aortopulmonary collaterals.

Most neonates with TOF are asymptomatic at birth, and cyanosis may be the only sign; this is often undetected if there is a PDA or in milder forms of TOF. In neonates with significant RVOTO, the cyanosis is obvious. In those with severe RVOTO or pulmonary valve atresia, the pulmonary blood flow is dependent on the patency of the ductus arteriosus. The neonates quickly become hypoxic as the PDA starts to close and require PGE₂ infusion to maintain systemic oxygenation.

Cyanotic spells are episodes of severe hypoxia and can be seen in newborns with moderate-to-severe RVOTO. The exact mechanism of these spells is unclear but may be multifactorial; the decrease in systemic vascular resistance and infundibular muscular hyperactivity are thought to be important.

Most neonates with TOF who have well-balanced systemic-to-pulmonary blood flow and systemic arterial oxygen saturation above 85% are discharged and have elective surgery between 2 and 6 months of age. The neonates who are on PGE₂ and who have cyanotic spells require surgical intervention in the neonatal period.

Clinical examination often reveals a systolic ejection murmur and a soft second heart sound. A continuous murmur of a PDA may be present. Chest x-ray (Figure 18-7) and ECG are often not diagnostic in neonates. Echocardiography (Figures 18-8 and 18-9) is the mainstay of diagnosis. With this modality, the diagnosis can be accurately established and all other morphologic features clearly defined except the details of pulmonary blood supply in patients with hypoplastic PAs or those with pulmonary atresia. In these neonates, cardiac catheterization and angiography or CT angiography is indicated.

Management

Most neonates with TOF do not require any intervention other than a period of observation until the PDA closes to ensure that they have adequate antegrade pulmonary blood flow to maintain systemic arterial oxygen saturation (preferably above 85% on room air).

If the neonate has cyanotic spells, aggressive medical management is immediately indicated. These spells are often amenable to maneuvers to increase systemic vascular resistance (knee-to-chest position), volume administration, sedation, and sometimes β-blockers. Any cyanotic spell would indicate early surgery. If the cyanotic spells are frequent or difficult to manage, then emergency surgery may be indicated. However, in neonates, often PGE₂ infusion can reopen the closed PDA and stabilize the patient. In neonates who are PDA dependent from birth, surgery is indicated within a few days after birth. The small subset of patients with major aortopulmonary collaterals and multiple sources of pulmonary blood flow most often do not require surgery in the neonatal period unless they have pulmonary overcirculation or significant hypoxia.

Surgery

Initial surgical management of TOF can be either palliative or reparative. Alfred Blalock, at the persuasion of Helen Tausig, performed the first palliative systemic-to-PA shunt, widely known as the Blalock-Tausig shunt (BT shunt) to increase the pulmonary blood flow to improve the hypoxia. In this operation, the subclavian artery was transected distally, turned down, and anastomosed to the right or left PA. This historic surgery marked the emergence of cardiac surgery for congenital heart defects. Alternative shunts, such as Potts and Waterston shunts, also were advocated but fell out of favor because of complications. The modified BT shunt with the use of an expanded polytetrafluoroethylene (ePTFE) tube graft or a central aorta-to-pulmonary shunt with an ePTFE tube graft is widely practiced for palliation of not only TOF but also many other forms of congenital heart defects with decreased pulmonary blood flow.

In the current era, repair not palliation even in neonates is preferred by many large centers. Palliation with shunts carries a higher mortality than repair and has the potential for PA distortion and shunt occlusion or thrombosis, resulting in interstage morbidity or mortality.

Surgical repair consists of patch closure of VSD with an RVOT procedure. The RVOT procedure varies depending on the size of the pulmonary annulus (Figure 18-10). If the pulmonary valve annulus is better than a z score of −2 to 2.5, then pulmonary valve commisurotomy and main PA enlargement along with infundibular muscle resection are performed. This results in little or no pulmonary insufficiency and no or mild pulmonary stenosis.

On the other hand, if the pulmonary valve is hypoplastic, a transannular patch RVOT augmentation is performed. This by definition means cutting across the pulmonary valve annulus, which results in pulmonary insufficiency. To avoid pulmonary insufficiency, some surgeons create a monocusp pulmonary valve from autologous pericardium or prosthetic material. The longevity of such monocusps is unreliable.

In patients with TOF with pulmonary atresia, a conduit (mostly a valved homograft conduit) is used to create continuity between the RV and PAs.

Outcomes

The surgical results of repair of TOF in the neonatal period have improved consistently since the 1990s.^{20, 21, 22, 23, 24, 25, and 26} In large centers, the mortality is less than 1% to 2% for repair in the neonatal period, thereby avoiding palliation. In comparable neonates, the mortality and morbidity of a palliation are equal to or worse than repair, hence the shift toward repair rather than palliation. However, in asymptomatic neonates, whether neonatal repair is really a good choice is controversial. Our approach is to perform an elective repair around 2 months of age in the asymptomatic group. Over the long run, many of these patients will require a pulmonary valve replacement or a conduit replacement if one has been used in the neonatal repair.

TRUNCUS ARTERIOSUS

In persistent truncus arteriosus (TrA), a single arterial blood vessel arises from the heart. A large VSD is almost always present in this condition with very rare exception. The PAs arise from this main arterial trunk, which then continues as the ascending aorta.

Morphology

Morphologically,^{27, 28, and 29} the TrA is classified²⁷ simply as type I when the main PA arises from the left lateral aspect of the truncus and divides into right and left PAs, type II when the right and left PAs arise as separate orifices but are close to each other from the left posterolateral aspect of the truncus, and type III when the right and left PAs arise separately from the right and left lateral sides of the truncus, respectively. This classification has no bearing on the outcomes but has implications in surgical reconstruction of the PAs.

Truncal valve morphology is variable. Most often, the valve is tricuspid but can also be bicuspid or quadricuspid. More important than the morphology of the valve is its function. Truncal valve regurgitation is seen in nearly a third to half of the patients and is moderate to severe in about 15% to 20%. True truncal valve stenosis is uncommon; more often, it is flow related.

Ventricular septal defect is almost always a subtruncal conoventricular defect and is unrestrictive. Occasionally, it is perimembranous, and additional muscular defects may be present. Coronary artery anomalies are common and seen in up to 60% of patients. In about 5% of patients, the aortic arch is interrupted; this is the only subgroup of patients who have a PDA. Rarely, the aortic arch is right sided, and in these patients tracheobronchial compression may be present.

Clinical Presentation, Pathophysiology, and Diagnosis

The most common presenting feature in the neonate is cyanosis. In neonates who present, late signs of congestive heart failure (CHF) are predominant, and the cyanosis may be minimal.

There is almost complete mixing of systemic and pulmonary venous blood, and pressures in both ventricles are identical. The level of oxygen saturation in the systemic circulation is proportional to the magnitude of pulmonary blood flow (PBF), which is dependent primarily on PVR and the size of the PAs. When the PBF is large, the patient is minimally cyanotic but may develop CHF because of excessive volume overload placed on the ventricle. When the PVR is high in the early neonatal period, the patient is cyanotic and does not develop CHF. In general, the neonate will start to develop pulmonary overcirculation within a few days after birth as the PVR continues to drop. As the PVR drops, patients develop CHF because of increasing PBF, and for a while the cyanosis abates until such time that pulmonary interstitial edema results in pulmonary venous desaturation.

Physical examination reveals varying degrees of cyanosis, depending on the magnitude of PBF. A heart murmur of the VSD is rarely audible because it is often large, and there is no pressure gradient between the 2 ventricles. If truncal valve regurgitation is significant, an early diastolic murmur may be heard. The ECG usually shows combined ventricular hypertrophy. The QRS complexes in all precordial leads are similar (poor R/S progression).

Chest x-ray (Figure 18-11) findings are consistent with the magnitude of PBF. In the early neonatal period, it may be relatively normal. Within a few days with increasing PBF, the chest x-ray shows signs of pulmonary congestion. Rarely, if the neonate has persistent pulmonary hypertension, the lung fields may look normal or hypoperfused.

The echocardiogram (Figure 18-12) is the gold standard for diagnosis of TrA. Often, it is the only diagnostic modality needed before surgery. Occasionally, it may be necessary to do a CT angiogram or cardiac catheterization to delineate the coronary anatomy or obtain hemodynamic data.

Management

In the neonatal period, these patients do not need any active management other than avoiding inhaled oxygen. As the PVR drops and CHF begins, anticongestant therapy may be needed. But, in the current era, surgical repair is undertaken within the first week of life.

Palliative surgical treatment of bilateral pulmonary banding is no longer practiced; instead, a complete repair is the surgical treatment of choice.

The surgical procedure (Figure 18-13) consists of closure of the VSD, detaching the PAs from the truncal vessel, and placement of the RV-to-PA conduit. The conduit can be valved or nonvalved³⁰ and either a homograft or a bioprosthetic. The truncal vessel from where the PAs are detached is reconstructed with a patch.

In patients with associated interrupted aortic arch, the arch reconstruction is performed with a direct anastomosis of the descending aorta to the ascending aorta with or without a patch to augment the reconstruction.

If the truncal valve regurgitation is more than mild, often an attempt is made to repair the valve; fairly good success is achieved. The need for neonatal truncal valve replacement is uncommon.

The surgery is performed on cardiopulmonary bypass with or without deep hypothermia and with or without circulatory arrest based on the surgeon’s preference.

Results

The results of repair of TrA have improved over the last few decades; currently, the early mortality is below 5% in most centers.^31,32 The major risk factor for mortality is severe truncal valve regurgitation. Early reoperation for progressive truncal valve regurgitation is not uncommon and may be needed in 5% to 15% of patients within the first year after surgery.^{31, 32, 33, 34, and 35}

HYPOPLASTIC LEFT HEART SYNDROME

Introduction

Hypoplastic left heart syndrome (HLHS) is a spectrum of lesions, which are characterized by hypoplasia or underdevelopment of left heart structures: LV, aortic valve, mitral valve, ascending aorta, and aortic arch. At one end of the spectrum is an isolated hypoplastic aortic arch, and at the other end of the spectrum is severe hypoplasia of the LV, atresia of the aortic and mitral valves, and very hypoplastic ascending aorta. However, in practice, the term HLHS more commonly is used to describe a constellation of these morphologic features that together necessitate a Norwood operation.

Morphology

Broadly, HLHS^36,37 can be divided into 4 categories, all of which have the common feature of hypoplastic LV (which by definition is unsuitable to function as an independent ventricle) and varying degrees of hypoplasia of the ascending aorta. The 4 subcategories are (1) aortic stenosis and mitral stenosis; (2) aortic atresia and mitral atresia; (3) aortic stenosis and mitral atresia; and (4) aortic atresia and mitral stenosis. Although there is no significant difference in outcomes, the subset of aortic atresia and mitral stenosis is considered higher risk because of the presence of a hypertensive LV and sometimes significant communication between the LV and coronary arteries and rarely LV-dependent coronary arteries. On the other hand, the subset of patients with aortic and mitral stenosis with a small but functioning ventricle are at the good end of the spectrum. These patients often have some antegrade blood flow through the aortic valve. Hypoplasia of the ascending aorta is more severe in patients with aortic atresia, and it is often less than 2 mm in diameter.

The more important factors that make HLHS high risk are RV function, the presence of moderate or severe TV regurgitation, and intact or severely restrictive atrial septum, resulting in pulmonary venous obstruction. Patients in this group are critically ill after birth and require immediate postnatal catheter or surgical intervention. In addition, the presence of any significant noncardiac abnormalities are unfavorable for survival of these neonates.

Clinical Presentation, Pathophysiology, and Diagnosis

Neonates who are undiagnosed prenatally may be overlooked in the period immediately after birth. As the PDA starts closing, cyanosis becomes more apparent, and symptoms of low cardiac output begin. If unrecognized, the patients soon go into circulatory shock because of low cardiac output. Closure of the ductus arteriosus to any significant degree is incompatible with life unless PGE₂ is started immediately.

Patients with aortic and mitral stenosis with some antegrade blood flow in the ascending aorta are more fortunate in this regard.

In HLHS, there is complete mixing of oxygenated and deoxygenated blood at the atrial and ventricular levels. The mixed blood is ejected through the pulmonary valve (some through the LV to the aorta in the subset of patients with aortic and mitral stenosis), and the systemic circulation is dependent on the patency of the ductus arteriosus (Figure 18-15A). In most patients, even the coronary and cerebral blood flow is retrograde from the PDA. The PVR of the pulmonary blood flow increases at the expense of systemic blood flow. If unrecognized tachypnea, CHF, and low cardiac output follow, they result in metabolic acidosis, multiorgan failure, and eventually death.

If untreated, most patients with HLHS die within the first week, and 90% of them do not survive beyond the first 2 weeks of life.

Diagnosis is established or confirmed by echocardiography, which is the mainstay of diagnosis. Cardiac catheterization is indicated if there is suspicion of LV coronary sinusoids or to define coronary anatomy. Rarely, other modalities such as CT angiogram or magnetic resonance imaging (MRI) are needed to define other associated defects, such as venous anomalies or tracheal or diaphragmatic abnormalities.

Management

Immediate medical attention is essential for establishing stable hemodynamics and ensuring survival. Once the diagnosis is made, the neonate is started on PGE infusion. If necessary, mechanical ventilation is also instituted. Often, this is planned because of prenatal diagnosis. In patients with intact or a severely restrictive atrial septum, the neonate is immediately taken to the cardiac catheterization lab, and ASD creation or enlargement with a stent is performed.

All associated metabolic defects are corrected, and blood transfusion to raise the hematocrit may be needed. It is necessary to correct any pulmonary overcirculation. The neonate should be on room air, and if ventilated, maintaining the PaCO₂ in the range of 50 to 55 mm Hg is helpful. Despite these measures, if the neonate is still overcircualting, especially if there is clinical evidence of systemic hypoperfusion, early surgery is indicated.

The surgical management for a long time has been a Norwood procedure³⁸ (Figure 18-14B), which involves creating a neoaorta using the native pulmonary outflow tract, providing controlled pulmonary blood flow through a systemic-to-pulmonary shunt (often a modified BT shunt), and atrial septectomy. A modification of the Norwood procedure was introduced by Japanese surgeons and is often referred to as the “Sano or Kishimoto shunt”; it is an RV-to-PA shunt instead of a BT shunt.³⁹ Because this is systolic-only shunting of blood in the PAs, it is believed to be more beneficial, especially in the early postoperative period, because there is no diastolic runoff into the shunt and coronary perfusion is better preserved. Currently, most surgeons and institutions prefer this approach.

More recently, another approach to neonatal management of HLHS called the hybrid approach has been introduced.⁴⁰ This approach involves avoiding a Norwood procedure in the newborn period. Instead, the neonate undergoes bilateral branch PA banding and at the same time (in hybrid catheter lab/operating room suites) or immediately thereafter stenting of the PDA and, if needed, the atrial septum. In essence, it is a way of replacing PGE therapy and controlling pulmonary blood flow. In Japan, oral PGE is used instead of a PDA stent, which probably is a better approach because it avoids all stent-related problems. This approach is not widely accepted yet but has its place, especially in neonates at high risk for whom avoiding cardiopulmonary bypass in the neonatal period is deemed beneficial: neonates with depressed ventricular function, associated significant noncardiac abnormalities, intact atrial septum, cerebral bleeding, and so on.

Outcomes

Surgical outcome of neonates with HLHS has steadily improved over the last few decades.^{41, 42, 43, and 44} More recent reports with a standard Norwood procedure or with an RV-to-PA shunt suggest a survival rate of over 90%.^41,42 A recent report in the New England Journal of Medicine from a randomized multicenter study comparing the Norwood procedure with the BT shunt versus the Norwood procedure with an RV-to-PA shunt appeared to favor the latter approach. The results of hybrid approach have been variable but have a high incidence of multiple interventions before the second stage. Overall, about 70% to 85% of hospital survivors of the Norwood procedure make it to the subsequent stage of cavopulmonary shunt. Home monitoring programs between stage I and stage II have also improved the survival interval.⁴⁴

PULMONARY VALVE ATRESIA WITH INTACT VENTRICULAR SEPTUM

Introduction

With rare exceptions, pulmonary valve atresia with IVS occurs with situs solitus and normal atrioventricular and ventriculoarterial connections. Pulmonary valve atresia with IVS is characterized by (1) complete obstruction of the pulmonary valve, (2) 2 distinct ventricles, (3) intact ventricular septum, and (4) a patent tricuspid orifice. Pulmonary valve atresia with IVS is a rare lesion, accounting for about 1%–1.5% of all congenital heart defects. The exact cause of this lesion is not known. The presence of abnormalities in the pulmonary valve without abnormalities in the aortic valve suggests that the etiology occurs after the valve cusps have formed. The majority of the cases have well-developed, fused pulmonary cusps with the typical triradiate appearance. The PA diameter is almost always normal in size in pulmonary valve atresia with IVS, and the ductus arteriosus is invariably present and is normal.

Morphology

Although the pulmonary valve lesion is presumably the primary event, much of the morbidity and mortality of this condition results from the severe secondary morphologic changes.^{45, 46, and 47} Marked morphologic heterogeneity is the hallmark of this lesion. All the secondary morphologic abnormalities in pulmonary valve atresia with IVS occur proximal to the right ventriculoarterial junction, in contrast to pulmonary atresia with a VSD, for which the major abnormalities occur distal to this junction.

The pulmonary valve is often well formed with definable but fused commissures. Bicuspid and quadricuspid valves are rare. However, not uncommonly the ventriculoarterial junction may be fibrous, which is presumed to be a remnant or pulmonary valvular tissue or imperforate fibrous tissue overlying muscular infundibular atresia.

An interatrial communication is virtually always present, most commonly a stretched foramen ovale (PFO). A true secundum ASD is present in about 20% of cases,²⁹ and in about 5%–10% of cases, the interatrial communication is restrictive, with the septum primum bulging into the left atrium.²⁶ The right atrium is often dilated, with the degree of dilation often proportional to the severity of tricuspid regurgitation.

Typically, the TV is smaller than normal, but it may range from the Ebstein anomaly with an enlarged dilated annulus on the one hand to an extremely stenotic valve on the other. In the Congenital Heart Surgeons Society (CHSS) study,²⁸ the median z value of the tricuspid annulus was −2.2 (the z value represents the normalized tricuspid annulus diameter, with 0 being normal³⁰ and the values above and below it representing the number of standard deviations from the normal). The size of the TV correlates well with the RV cavity size and is important in the prognosis of pulmonary valve atresia with IVS; it is discussed further in this chapter. Varying degrees of TV dysplasia are seen. In about 5%–10% of cases, the Ebstein deformity of the TV is present. Functionally, the TV may be regurgitant, stenotic, or both. Some degree of tricuspid regurgitation is present in most cases, with severe tricuspid regurgitation present in about 25% of cases.²⁸

The RV is hypertrophied with a reduced cavity in 90% of cases, severely so in about 60% of cases. In about 5%–10% of cases, an enlarged and dilated RV is found in association with more severe degrees of tricuspid regurgitation and with an Ebstein anomaly. Even the smallest RVs are thought to have all 3 components; however, the massive hypertrophy may obliterate the trabecular or outlet parts. Associated diffuse fibrosis of the hypertrophied ventricular muscle may be present, and in severe cases, varying degrees of endocardial fibroelastosis are seen.

Coronary artery abnormalities and RV myocardial sinusoids are common in pulmonary valve atresia with IVS. RV sinusoids are present in about 50% of cases. These fistulous communications seem to be most prominent with small hypertensive RVs, occurring in 8% to 55% of reported cases. These fistulas from the coronary artery to the RV are present in the majority of cases in which sinusoids are present, and the prevalence of these lesions correlates inversely with TV diameter, RV cavity size, and the degree of tricuspid incompetence. In about 20% of these cases, the coronary circulation or some important part of it is solely derived from the RV. This is described as RV-dependent coronary circulation.

The PAs nearly always branch normally and are of normal size, with significant hypoplasia present in only about 6% of cases. The ductus arteriosus is almost always present, and postnatal survival is dependent on ductal patency.

Clinical Presentation, Pathophysiology, and Diagnosis

The infant born with pulmonary valve atresia with IVS is compromised physiologically almost immediately. The atretic pulmonary valve causes an obligatory dependence on patency of the ductus arteriosus for pulmonary blood flow. An ASD allows for complete mixing of deoxygenated and oxygenated blood. Pulmonary blood, and hence systemic oxygen delivery, depends on the patency of the ductus arteriosus.

Systemic arterial blood pressure usually shows a somewhat widened pulse pressure, secondary to runoff through the ductus arteriosus into the pulmonary circuit. RV pressure tends to correlate inversely with the degree of tricuspid insufficiency. RV pressure is typically systemic or suprasystemic in the small hypoplastic RV but may be lower in a completely decompensated dilated RV with profound tricuspid regurgitation.

In infants with pulmonary valve atresia with IVS, the extremely high pressure in the RV reduces coronary flow, which results in chronic ischemic changes, especially in the subendothelial layers, and may account for the subendocardial fibrosis of the RV seen in many of these patients.

In cases of RV-dependent coronary blood supply (Figure 18-15A, 18-15B), the myocardium is supplied partly or completely by desaturated blood at systemic-to-suprasystemic systolic pressures and relatively low diastolic pressures. The extremely marginal coronary reserve in these patients can be easily compromised if RV systolic pressure is reduced by any means.

Most infants born with pulmonary valve atresia with IVS are at term gestational age. Signs of cyanosis and hypoxia occur variably from a few hours to several days after birth and depend on ductal flow. However, the majority (over 90%) of patients with pulmonary valve atresia with IVS present in the first 3 days of life as the ductus arteriosus begins to close. Currently, most often a fetal diagnosis is made, and PGE is instituted immediately after birth.

Chest roentgenograms in pulmonary valve atresia with IVS vary with anatomic type. In cases with a tiny RV and little or no tricuspid insufficiency, the heart is normal in size. The vascularity is reduced, normal, or occasionally increased, depending on the patency and size of the ductus arteriosus and the PVR. If the RV is normal or large with tricuspid insufficiency, the overall heart size is increased, and the enlarged right atrium gives considerable convexity to the right heart border.

Echocardiography allows a definitive and detailed diagnosis (Figure 18-16). Morphologic details of the RVOT, RV cavity, TV, atrial septum, and ductus arteriosus patency can be evaluated thoroughly and accurately. RV dependency on coronary blood flow cannot be reliably assessed by echocardiography, and cardiac catheterization and angiocardiography are necessary.

If untreated, pulmonary atresia with an intact septum carries a dismal prognosis. Within 2 weeks of birth, 50% of patients die, and by 6 months of age, 85% succumb. Death commonly results from severe metabolic acidosis caused by hypoxia following ductal narrowing or closure.

Management

As soon as the diagnosis is made, an infusion of PGE₁ (0.05 to 0.1 mg/kg/min) is started to maintain patency of the ductus arteriosus. Mechanical ventilation and inotropic support may be required in about one-third of patients.

If the diagnosis is delayed, profound cyanosis secondary to ductal constriction may be the mode of patient presentation. In this case, aggressive resuscitation with PGE₁, sodium bicarbonate, inotropic support, and mechanical ventilation may be necessary. Patients should be adequately stabilized whenever possible and thoroughly evaluated before performing the initial surgical procedure.

Catheter Intervention

During cardiac catheterization, a balloon atrial septostomy should be performed if deemed necessary to allow unrestricted right-to-left shunt. In selected cases of membranous pulmonary valve atresia with well-formed cusps, balloon valvotomy has been accomplished with acceptable initial results. Prostaglandins are generally weaned gradually over hours to days. This approach is an exception rather than a standard approach, and further follow-up is necessary to determine its success. More recently, radio-frequency and laser-guided pulmonary valve perforation and dilation have been undertaken successfully in a select group of patients.

Surgical Management

The ideal outcome for a patient with pulmonary atresia with IVS is completely separated in series 2-ventricle circulation. The central issue in achieving this is whether the RV can function as the sole provider of pulmonary blood flow at normal filling pressures. The primary goal of neonatal surgical management is to minimize mortality. The secondary goal should be to promote growth of the RV, thereby optimizing the chances of 2-ventricle circulation.

The following morphology-specific treatment guidelines seem to give the best chances of fulfilling the goals mentioned, with these guidelines based on the data from the CHSS study⁴⁸:

In a small subset of patients for which the TV diameter (z = 0 to −2) and RV cavity approach normal size, it may be ideal to perform an RVOT procedure (balloon or surgical pulmonary valvotomy or transannular patch) alone (Figure 18-17). With any of these procedures, profound postoperative cyanosis indicates the need for a shunt. This is likely to be necessary in slightly less than half of patients by 1 month of life.

For the patient with mild-to-moderate TV annular hypoplasia (z = −2 to −3), the goal of 2-ventricle circulation is achievable. However, the likelihood of this outcome decreases as the TV annular size decreases. The RVOT procedure with concomitant shunt is favored.

For the subset of patients with severe TV annular hypoplasia (z = −3 or less), the preferred procedure is a shunt alone because an ultimate 2-ventricle repair is unlikely in this subset. In the CHSS study, no patient with a TV annulus size less than 3 standard deviations below normal (z = ≤3) has achieved a 2-ventricle repair.

In any patient with RV-dependent coronary circulation, RV decompression is contraindicated and shunt alone is the procedure of choice.

The subsequent surgical management of pulmonary valve atresia with IVS is also complex. It is generally accepted that 2-ventricle circulation with completely separated pulmonary and systemic circuits is ideal. But, it is also realized that some patients can never achieve this. Close follow-up is indicated in all patients irrespective of the initial procedure.

Results

The recent data from the CHSS study appear to be representative of general experience with this lesion.^{47, 48, 49, 50, 51, and 52} In this study, the overall survival was 81% at 1 month and 64% at 4 years. This study also showed that a TV with a small diameter and marked RV coronary artery dependency were important morphologic risk factors for death. In addition, 55% of the survivors required subsequent procedures, mainly to address the inadequacy of the original procedure. Although Fontan repairs and “one-and-a-half-ventricle repairs” have been successfully achieved in patients with pulmonary valve atresia with IVS, follow-up data are needed to identify the predictors of successful long-term outcome.

TRICUSPID ATRESIA AND OTHER FORMS OF FUNCTIONALLY SINGLE VENTRICLES

Introduction

Tricuspid atresia⁵³ is the lack of a direct connection between the right atrium and RV because of complete atresia of the TV. This atresia is most often muscular but can be membranous.

Morphology

In tricuspid atresia, the TV is usually completely absent or can be vestigial or Ebstenoid, but in all cases, there is no opening in the TV.⁵⁴ The right atrium is usually enlarged to some degree, and there is an unrestricted ASD. In patients without a VSD, the RV is severely hypoplastic, and the pulmonary valve is atretic or rudimentary. If there is a VSD, the RV and pulmonary valve are hypoplastic to varying degrees. The great arteries are normally related in the majority and transposed in about 20% to 30% of patients. In patients with TGA, there is a subgroup that has systemic subaortic obstruction without hypoplasia of the aortic valve and ascending aorta.

Other Miscellaneous Defects

Various forms of functionally single ventricles can cause cyanosis, although they are relatively rare. Embryologically, these single ventricles occur because of poor alignment of the common atrioventricular valve with the ventricles or incomplete septation of the ventricle chambers. These abnormalities in the fetal period of life end in double-inlet ventricles (usually, a double-inlet LV, the most common form of single ventricle), tricuspid atresia, mitral atresia, unbalanced atrioventricular canal defect, and a functional single ventricle with heterotaxy syndromes (asplenia, polysplenia, or atrial isomerism).

Pathophysiology, Clinical Features, and Diagnosis

The common unifying feature of these lesions is complete mixing of deoxygenated and oxygenated blood in the single functional ventricle. Patients may or may not be dependent on the patency of the ductus arteriosus. Patients with severe pulmonary stenosis or atresia are PDA dependent. In the absence of significant pulmonary stenosis, there is often pulmonary overcirculation, and the cyanosis is mild. On the other side of the spectrum, there is obstruction to systemic blood flow, and these patients have physiology similar to those with HLHS.

The lung fields on chest x-ray reflect the pulmonary blood flow status. Also, the atrial and visceral situs can be discerned. Echocardiography (Figure 18-18) is the mainstay of diagnosis and often is enough to plan surgical management. These neonates often have abnormal systemic and pulmonary venous connections that have to be delineated accurately. A CT angiogram can accurately define the venous anatomy in addition to pulmonary situs and visceral situs. Cardiac catheterization may be necessary in some patients, especially if there is potential for therapeutic palliative intervention such as balloon dilation of pulmonary stenosis or ductal stenting, which some institutions prefer.

Management

For a neonatologist, once the diagnosis is made, the next step is to assess the patient and determine the pathway of clinical management. Despite the complexity of morphology in terms of various atrial, ventricular, and venous abnormalities, the most important thing to consider is assessment of pulmonary blood flow: rule out any systemic outflow obstruction and pulmonary venous obstruction (including at the level of the atrial septum).

Assessment of pulmonary blood flow: Occasionally, a patient has just the appropriate amount of pulmonary blood flow because of natural stenosis in various levels of pulmonary stenosis. However, many of them present with either high or low oxygen saturation, depending on the balance between the systemic and PVR. The low arterial oxygen saturation level can hinder normal growth and impair organ function. The high arterial saturation level results in pulmonary hypertension and impaired ventricular function. Generally, an arterial oxygen saturation level between 75% and 85% indicates a reasonable amount of pulmonary blood flow in terms of protection of the pulmonary vascular bed and ventricular function.

In addition to arterial oxygen saturation level, the plain chest x-ray helps assess pulmonary blood flow. A congested lung field and an enlarged heart imply pulmonary overflow and an oligemic lung field, and a small heart implies diminished pulmonary flow, with the exception of pulmonary venous pathway obstruction, which shows a congested lung field with diminished blood flow. Echocardiography is essential to determine the segmental classification of the patient’s cardiac anatomy. Echocardiography should carefully examine any levels of obstruction in systemic and pulmonary circulation.

Assessment of systemic outflow obstruction: Clinically, the cyanosis is variable and depends on the amount of pulmonary blood flow. More important, the neonate should be assessed for signs of systemic hypoperfusion, which necessitates institution of PGE₁. Systemic outflow obstruction can be accurately assessed by echocardiography and cardiac catheterization is usually not necessary.

Assessment of pulmonary venous obstruction: Pulmonary venous obstruction, if severe, can be catastrophic and should be ruled out. A cyanotic patient in respiratory distress should prompt immediate attention. Chest x-ray shows signs of pulmonary venous congestion, and echocardiography is almost always diagnostic, but a CT angiogram or cardiac catheterization may be necessary to delineate the pulmonary venous anatomy. Occasionally, if the pulmonary venous obstruction is at the level of the atrial septum, a balloon septostomy is urgently indicated.

Palliative Surgical Intervention in the Neonatal Period and Outcome

The goal of intervention for all forms of single-ventricle physiology has 2 prongs: (1) achievement of an adequate balance between systemic and pulmonary blood flow; and (2) relief of obstructed systemic cardiac output.

Inadequate Pulmonary Blood Flow

In neonates with low saturation, it is critical to assess the cause of pulmonary blood flow obstruction. It can be one of the following or a combination of them: (1) pulmonary outflow obstruction, (2) pulmonary venous obstruction, and (3) poor mixing at the atrial level.

The most common cause of inadequate flow is pulmonary outflow obstruction at various levels. To increase the pulmonary blood flow, a systemic-to-pulmonary shunt, either a modified Blalock-Tausig shunt (Figure 18-19) or a central shunt is employed. Usually, we can perform this procedure without cardiopulmonary bypass unless other intracardiac procedures are necessary. It is important to select the appropriate size shunt to achieve an arterial oxygen saturation of 80%–85%. An oversize shunt can create pulmonary overcirculation, which results not only in systemic hypoperfusion but also in volume overloading of the ventricle. It impairs myocardial contractility subsequently and causes long-term cardiac dysfunction. The shunt is also known to result in scarring and distortion of the PAs. Even though the Blalock-Tausig shunt was introduced almost 70 years ago, the mortality remains relatively high in a patient with a single ventricle (hospital mortality is 15% in those with a single ventricle vs 3% in a biventricular patient).

Particularly in the case of patients with heterotaxy syndrome, it is known that they may present with a severe degree of cyanosis because of an obstructed TAPVR. To prevent the damage in the pulmonary parenchyma and optimize development of the PA, it is important to repair the TAPVR soon after the diagnosis is made. This anomaly significantly complicates the care of a patient, and although early survival in these patient has improved, intermediate survival is still approximately only 50%.³

In patients with stenosis or atresia of the left atrioventricular valve, it is obligatory to have an unobstructed left-to-right flow at the atrial septal level. If the ASD is not adequate, it can cause pulmonary venous hypertension, resulting in cyanosis. For these patients, atrial septectomy is indicated. This can be performed with relatively low mortality either as an isolated procedure or combined with a systemic-to-pulmonary shunt or PA banding.

Excessive Pulmonary Blood Flow

Neonates with single-ventricular physiology without any PA or venous obstruction will develop pulmonary overcirculation as the PVR declines in the first couple of weeks of life. Excessive pulmonary flow can result in persistent pulmonary hypertension or impaired ventricular function, which make subsequent right heart bypass procedures, such as a Glenn or Fontan operation, difficult. Usually, to control the excessive pulmonary flow, creation of stenosis in the pulmonary trunk by banding is indicated (Figure 18-20). It is crucial to assess the status of the LVOT before proceeding to PA banding. As stated, in a single ventricle, pulmonary circulation and systemic circulation are parallel. Excessive pulmonary blood flow can be caused by either low PVR or high systemic vascular resistance. The PA banding can be performed without cardiopulmonary bypass in a safe manner. The degree of the banding is usually decided based on intraoperative echocardiography, pressure measurement, and oxygen saturation. The target oxygen saturation is usually 80%–85% under room air. According to a recent study of patients with single-ventricle physiology who underwent PA banding, the actual overall survival was 84% at 1 year and 76% at 5 and 15 years.⁴

In case of LV outflow obstruction, the patient instead should have systemic outflow augmentation procedures such as a Norwood or Damus-Kaye-Stansel procedure.

Systemic Outflow Obstruction

Systemic outflow obstruction can cause 2 problems: development of ventricular hypertrophy and pulmonary overcirculation. Ventricular hypertrophy results in ventricular dysfunction and late arrhythmia. It is important to address this problem early in life; otherwise, it will have a significant impact on patient mortality and morbidity. In the case of subaortic obstruction, the Damus-Kaye-Stansel procedure (the creation of an anastomosis between the proximal pulmonary trunk and the ascending aorta) has been employed. For LVOTO associated with a hypoplastic arch, a Norwood-type operation that requires major reconstruction of the arch in addition to the pulmonary trunk and ascending aorta anastomosis has been used. In either of these surgeries, pulmonary blood circulation is ensured by placing a graft between systemic and PA (or ventricle) circulation.

Results

The results of surgery are in general best for patients with tricuspid atresia who require pulmonary banding (over 95% survival) and worst with obstructed pulmonary venous drainage (up to 50% to 75% early mortality).^{55, 56, and 57} The subsequent management of these patients requires a cavopulmonary shunt at 4 to 6 months of age and a Fontan procedure between 18 months and 4 years.

REFERENCES

SUGGESTED READING

INTRODUCTION

This chapter focuses on noncyanotic congenital heart disease with a basic description of the epidemiology, embryology, clinical manifestation, diagnostic testing, management, treatment, and prognosis of each lesion. The intent is to provide a framework for the major types of noncyanotic congenital heart disease, ranging from septal defects, left ventricular outflow tract (LVOT) obstruction disease, and right ventricular outflow tract obstruction disease. The chapter forms a guide for managing neonates with these common heart conditions.

SEPTAL DEFECTS

Atrial Septal Defect

The atrial septal defect (ASD) is one of the first forms of congenital heart disease that was corrected surgically. It represents a communication between the left and right atria and does not usually manifest in the neonatal period unless there is associated congenital heart disease, which usually makes it difficult to diagnose. There are 3 major types: secundum ASD, primum ASD, and sinus venosus ASD. The primum ASD is discussed as a part of the atrioventricular canal (AVC) defect (Figure 19-1).

Epidemiology

The ASD represents the second-most-common form of congenital heart disease behind the ventricular septal defect (VSD). The occurrence is between 3% and 4.1% of 1000 live births^1,2 and 7% and 15% of all congenital heart disease cases.^3,4 For defects that are larger and measure over 5 mm in diameter, there tends to be a female predominance.^5,6 The secundum ASD is by far the most common type (Table 19-1). Nearly 1 of every neonates will have an atrial communication that is difficult to distinguish from a patent foramen ovale.⁷ Approximately 15% of trisomy 21 patients will have a secundum ASD, and 1% of ASD patients will have Holt-Oram syndrome.⁸ Of note, patients with Holt-Oram tend to have very large ASDs and can have a common atrium with no wall separating the atria.

Pathophysiology

Patients with ASDs that are hemodynamically significant tend to have problems later in life and do not present in the neonatal period. Specifically, there is a chronic left-to-right atrial shunt that enlarges the right atrium and right ventricle. This shunt increases blood flow to the pulmonary arteries, which chronically can change the pulmonary vascular bed, leading to pulmonary hypertension. Approximately 22% of ASD patients will develop pulmonary hypertension in adulthood if the ASD is left unrepaired, and 15% will have elevated pulmonary vascular resistance.⁹ Eisenmenger syndrome develops if a chronic left-to-right shunt lesion causes severe pulmonary vascular changes such that there is significant elevation in the pulmonary vascular resistance and a reversal of the shunt. Thus, blood would flow from the right atrium to the left atrium, resulting in arterial hypoxemia. Eisenmenger syndrome occurs 14% of the time in patients with an ASD.⁹ Again, if left untreated another complication is right heart failure from the chronic volume overload as well as atrial arrhythmias from right atrial distension.⁹ Fewer than 1% of infants with an isolated secundum ASD will develop significant symptoms that may lead to death.¹⁰

Infants can develop early right heart failure, which is presumably from a rapid drop in the pulmonary vascular resistance.¹¹ The degree of shunting is related to the relative compliance of the left ventricle in comparison to the right ventricle. As the resistance in the pulmonary bed drops, the right ventricular “stiffness” decreases, leading to the left-to-right shunt. Thus, ASD should be considered in the differential diagnosis of any infant with congestive heart failure or failure to thrive.¹²

The secundum ASD represents a defect in the flap of the foramen ovale where it is incompetent, leading to left-right shunting. The sinus venosus ASD, however, is quite separate and high, where the right pulmonary veins and superior vena cava drain; frequently, there is no associated shunting across the foramen ovale. Thus, anomalous drainage of the right pulmonary veins into the superior vena cava is associated with the sinus venosus ASD.

Regardless of the type of ASD, most patients are asymptomatic in early childhood; however, congestive heart failure symptoms begin before the age of 6 years in 84% of patients and, as mentioned, symptoms can develop during infancy if there is a rapid drop in the pulmonary vascular resistance.^9,11,13 The symptoms in the infant would include failure to thrive, tachypnea, feeding difficulties, and diaphoresis with feeds. Cyanosis would be unlikely because this defect does not produce Eisenmenger syndrome until adulthood. In the older patient, easy fatigability, syncope, and hemoptysis may also be present along with frequent pulmonary infections from the chronic left-to-right shunt. Unfortunately, 30% of children have only 1 or no typical physical sign from an ASD, which makes the diagnosis in the young child difficult.¹⁴

As a result of the extra volume of blood traversing the pulmonary valve, there is a relative pulmonary valve stenosis murmur. The systolic ejection-type murmur is present in 87% to 100% of the time.^14,15 In addition, extra volume across the tricuspid valve may lead to diastolic murmur from relative tricuspid stenosis in some cases. As a result of this volume-loaded right ventricle, the pulmonary valve closes later than the aortic valve throughout the cardiac cycle, resulting in the “fixed” split in S2, which is present 57% of the time.¹⁴ Again, the neonate presents a challenge because in most patients the right ventricle is not volume loaded since the pulmonary vascular resistance remains relatively high and the right ventricle is “stiff.” Thus, the physical examination findings may not be present during infancy.¹²

A few etiologies have been discovered for the ASD. The only reported maternal exposure associated with ASD is maternal alcohol consumption, which appears to double the risk of ASD.¹⁶ Mutations in the fetus NKX2.5 gene have been identified in patients with many forms of congenital heart malformations, and ASD is common among them.^17,18

Differential Diagnosis

Because the child with an ASD can have signs of congestive heart failure, other disease processes that cause congestive heart failure should be included in the differential diagnosis. Specifically, congenital heart disease that leads to a chronic left-to-right shunt should be considered, such as a VSD, patent ductus arteriosus, or an AVC defect. Infants with cardiomyopathy may also have the same symptoms noted for ASD. Finally, other noncardiac conditions that can cause congestive heart failure should also be considered, such as sepsis, severe anemia, or pulmonary infection.

Diagnostic Tests

Prior to the advent of echocardiography, the cardiac catheterization was used in patients with a clinical suspicion of ASD for diagnostic purposes, and repair was considered if the relative pulmonary blood was 50% greater than the flow across the aorta.³ The electrocardiogram (ECG) in the neonate and infant may not demonstrate the classic RSR′ pattern because this is a marker for volume load, and right ventricular hypertrophy is a common finding in normal neonates (Figure 19-2). Also, ECG findings are often missing in children with ASD.¹⁴

Currently, the echocardiogram remains the gold standard for the diagnosis of all types of ASD. In addition to identifying the type of ASD, this technique is used to guide transcatheter closure and evaluate the surgical repair of an ASD.

Management

The decision to close a secundum ASD depends on the size of the defect, the degree of shunting, and the evidence of right ventricular enlargement. Traditionally, if the relative flow across the pulmonary artery is 50% more than the flow across the aorta because of the ASD, then an intervention is recommended.³ Surgical closure or modern-day device closure with interventional cardiology of secundum ASDs is generally low risk and curative. The sinus venosus ASD is surgically repaired because there is no intervention available for this defect at this time.

In general, the closure of an ASD should be done in early childhood; however, as mentioned, there are cases where an infant would have evidence of congestive heart failure and secondary failure to thrive, which would warrant an earlier intervention.¹⁹ Infants can also safely undergo ASD device closure in the catheterization laboratory, which would avoid a sternotomy and cardiopulmonary bypass.²⁰

Spontaneous closure occurs in 26% of patients before the age of 2 years, and in general an ASD is unlikely to close after this age, which supports the idea of repair in early childhood.²¹ Ninety-eight percent of ASDs less than 3 mm in diameter in neonates close by 18 months of age, and defects greater than 3 mm take longer to close.^6,22 Thus, size of the defect at initial presentation has an impact on the spontaneous closure rate. The ASDs in premature infants take longer to close; however, an associated patent ductus arteriosus tends to close the ASD sooner, presumably because of elevated left atrial pressure, which causes the septum primum flap to abut against the septum, resulting in closure of the defect.⁶

Outcome and Follow-up

Death is rare in patients with unrepaired ASD; however, atrial arrhythmias in adult patients with chronic atrial distension from the left-to-right shunt is much more common.³ Cerebrovascular accidents are even rarer than mortality but still may occur.³ Most patients are not symptomatic until the third decade of life; however, intervention is recommended in early childhood.^3,9

With the advent of echocardiography and color Doppler, ASDs are recognized more readily at an earlier age. Over 70% to 80% of all secundum ASDs close spontaneously by 18 months of age.^1,5 A defect less than 3 mm in diameter has a nearly 100% spontaneous closure rate, while a defect greater than 8 mm is unlikely to close,^8,23 confirmed by later studies.^{24, 25, and 26}

Ventricular Septal Defect

The VSD represents a communication between the right and left ventricles and varies significantly in presentation. For the most part, the neonate may not have symptoms from a VSD even when it is large because flow across it relies on a drop in the pulmonary vascular resistance. The defect is classified by its location within the ventricular wall, the size, and the number of defects. Essentially, there are 3 major types: perimembranous, doubly committed subarterial (supracristal), inlet, and muscular (Figure 19-3). The perimembranous VSD lies superior and anterior within the region of the membranous septum, which is bordered by the tricuspid valve and aortic valve. The supracristal VSD is also anterior but represents a defect below the pulmonary and aortic valves. Both of these defects are outlet VSDs. The inlet VSD is a defect that is near the atrioventricular valves and located quite posteriorly. This defect is most commonly discovered with a complete atrioventricular canal (CAVC) defect, which is discussed further in this chapter. The muscular VSD represents a defect in the trabecular end of the ventricular septum and is bordered completely by muscle. Any combination of these defects may coexist; thus, the clinician should always be suspicious of multiple defects.

Epidemiology

The VSDs occur approximately in 0.95 of 1000 live births and represent the most common form of congenital heart disease other than bicuspid aortic valve. The majority of defects are perimembranous, ranging between 62% and 83%, followed by muscular defects, which vary between 9% and 12%.^{27, 28, 29, and 30} Supracristal defects are much less common and occur between 2% and 3% of the time.^27,29 Muscular defects are less likely to be associated with a syndrome or a karyotype anomaly.¹

Pathophysiology

The primary issue with the VSD is related to the degree of shunting from the left to the right ventricle. Multiple variables influence the degree of shunting and resultant symptoms from this type of defect. Specifically, the size and location of the defect are important in that small defects tend to protect against congestive heart failure. However, multiple small defects, known as a “Swiss cheese” VSD, may cause significant heart failure because of the collective size of all of the defects. Swiss cheese–type defects account for 0.5% of VSDs.²⁸ The other variable of importance is the relative resistance of the systemic and pulmonary vascular bed. In the neonatal period, the pulmonary vascular resistance is high; therefore, there is minimal shunting. As the pulmonary vascular resistance falls dramatically in the first few weeks of life, more left-to-right systolic shunting occurs across the defect. Because the relative pressures in diastole are similar between the ventricles, there is minimal diastolic shunting. Blood that shunts in systole enters directly into the main pulmonary artery; therefore, there is no nidus for right ventricular enlargement. The main pulmonary artery, left atrium, and left ventricle dilate with VSD physiology but not the right heart structures.

As the pulmonary vascular resistance drops, infants develop symptoms, which include tachypnea, feeding intolerance, failure to thrive, and diaphoresis.^27,31 However, 50% of infants may have no symptoms despite having a large defect. If the pulmonary vascular resistance fails to drop significantly, then the shunting and congestive heart failure symptoms would be minimal. Of note, premature infants tend to go into congestive heart failure much quicker than term infants; however, the proportion of patients in either group with these symptoms is the same.³¹ The pulmonary vascular resistance drops with age, as expected in the setting of a VSD, but the resistance is generally higher for larger VSDs.³¹

The VSD murmur is usually not heard in the first few days of life unless it is a small defect. In fact, the murmur typically occurs within the first week to month of life in most cases.³¹ Classically, the VSD’s murmur is holosystolic in that it blends with the first heart sound, which generally cannot be auscultated. In addition, there may be excessive flow across the pulmonary and mitral valves, which would lead to a relative stenosis murmur in systole and diastole, respectively. In the case of a large VSD, the murmur may be difficult to hear.

Spontaneous closure of the VSD has been noted for the perimembranous and muscular VSD through various mechanisms. Tricuspid valve tissue may adhere to the perimembranous defect, resulting in occlusion of the defect over time.^32,33 The aortic valve sinus of Valsalva may also occlude the defect over time; however, this may be associated with herniation or rupture of the sinus into the right ventricle or aortic insufficiency. The margins of the muscular defect become relatively small as the child grows and the interventricular septum thickens, which is believed to be the mechanism of spontaneous closure.

Many associations have been noted with the outlet VSDs. Specifically, there can be a subaortic membrane or ridge associated with the defect that causes stenosis.^28,34 As noted, aortic insufficiency is associated with perimembranous defects but is also associated with supracristal defects because of the lack of tissue supporting the subvalvar apparatus.^28,35 However, subacute bacterial endocarditis associated with having a high-velocity jet and endothelial damage has also been noted to occur in 6% of all VSDs and can lead to aortic insufficiency secondary to direct damage; this will only exaggerate the congestive heart failure symptoms.³⁶ Subacute bacterial endocarditis and aortic insufficiency tend to be manifestations of a VSD later in life; congestive heart failure begins in infancy. An additional association is double-chamber right ventricle, for which a callous formation develops on the opposing wall of the right ventricle, which causes subpulmonary valve obstruction. Any outlet VSD can have an association with a coarctation of the aorta, which is discussed further in this chapter. VSD has an association with other forms of more complex cyanotic congenital heart disease; discussion of this is beyond the scope of this chapter.

The associated noncardiac conditions include trisomy 21, the VACTERL (vertebral defects, anal atresia, cardiac defects, tracheoesophageal fistula, renal anomalies, and limb abnormalities) association of congenital defects, cleft palate, bronchopulmonary dysplasia, chondrodysplasia, Klippel-Feil syndrome plus omphalocele, and polysplenia syndrome.³⁷

Differential Diagnosis

Given that the VSD presents with signs of congestive heart failure in the infant after decreases in pulmonary vascular resistance, any other disease process that causes congestive heart failure must be ruled out. As with the ASD differential diagnosis, the left-to-right shunt lesions must be considered, such as AVC, patent ductus arteriosus, and aortopulmonary window. Also, as the pulmonary vascular resistance drops, infants with anomalous origin of the coronary artery from the pulmonary artery would present as well because of coronary ischemia and steal. These patients would present with heart failure symptoms as well. In addition, lesions that cause high-output failure can mimic symptoms of a VSD. These include and are not limited to sepsis, severe anemia, and hepatic and cerebral arteriovenous malformations.

Diagnostic Tests

Ascultatory findings may not be evident on large defects because a VSD murmur may not be present. The ECG will demonstrate left atrial enlargement and left ventricular hypertrophy in the setting of large defects; chest x-ray will show evidence of cardiomegaly with increased pulmonary vascular markings. These findings, however, are nonspecific, and the diagnosis is usually made by echocardiography.³⁸ In fact, detection and closure of a VSD can be determined by fetal echocardiography as well.^39,40 In the past, these defects were confirmed by cardiac catheterization, which is no longer necessary.

Management

Large VSDs need to be repaired during infancy, and the elevated pulmonary vascular resistance as a result of the chronic shunt should improve postoperatively.²⁷ There is no difference in outcome for large VSD closure in children less than 4 kg vs greater than 4 kg; thus, it is recommended to intervene early to prevent recurrent respiratory infection, failure to thrive, and feeding difficulties.³⁷

In the past, a pulmonary artery band (PAB) was positioned to limit pulmonary blood flow, and the VSD was closed as a separate procedure to minimize morbidity and mortality; however, VSDs are now closed in 1 step with primary closure regardless of the type. The indications for surgery include left heart failure, failure to thrive, feeding problems, and elevated pulmonary artery pressure. VSDs are usually closed through the right atrium^41,42 as opposed to a ventriculotomy, which can create a scar on the myocardium. For defects closer to the semilunar valves, repair can also occur through the pulmonary valve.⁴³ Multiple muscular VSDs can be closed primarily instead of with a PAB; however, if the septum is Swiss cheese, a PAB may be necessary because a patch across all of the defects may be difficult and may result in ventricular dysfunction.⁴⁴ After PAB placement, the defects may close spontaneously. Perventricular device closure of muscular VSDs in the cardiac catheterization lab may be an option in some select patients^45,46; however, closure of perimembranous VSDs was not available when this chapter was written. This option is attractive to avoid a sternotomy, PAB, or cardiopulmonary bypass.

Outcome and Follow-up

The natural history of a VSD is for spontaneous closure, reduction in size, or development of pulmonary vascular disease. Death in infancy is most probably related to congestive heart failure.⁴⁷ The overall mortality is approximately 3% in all patients.³⁶ In general, muscular defects tend to have less congestive heart failure, higher closure rate, and less need for operative intervention compared to outlet defects.⁴⁸

The natural closure rate for all VSDs is 22% to 36%.^31,33,49 The vast majority of defects that close do so before the eighth year of life and tend to be less than 6 mm in diameter.⁴⁹ Approximately 15% to 29% of perimembranous defects close compared to 57% to 65% of muscular defects.^1,28,50 Muscular defects tend to close during the first 6 to 12 months of life.⁵¹ The most common complications after cardiac surgery include a residual VSD, right bundle branch block, complete heart block, death, persistent pulmonary hypertension, cerebrovascular accident, or tricuspid valve regurgitation, which may be related to perimembranous patch closure. However, in a recent article, the surgical results for isolated VSD were noted to be good, with 0% reoperation for residual defect, 0.5% mortality, 99.5% of patients asymptomatic, and none had more than mild new-onset tricuspid valve regurgitation.³⁰

Atrioventricular Septal Defect

An atrioventricular septal, or canal, defect represents a malformation of the AVC whereby the crux of the heart does not develop, which potentially renders a primum ASD and inlet VSD. Thus, there is a spectrum of disease ranging from an isolated primum ASD with a cleft mitral valve to a CAVC defect with a large inlet VSD and primum ASD (Figure 19-4). As a result of these communications, patients can develop a chronic left-to-right shunt and atrioventricular valve regurgitation. As with other ASDs, a patient with an isolated primum ASD and cleft mitral valve does not usually present with heart failure in infancy; however, a CAVC can cause significant congestive heart failure in the first few months of life.

Epidemiology

The diagnosis of AVC defect often occurs with trisomy 21. In fact, about 50% of patients with trisomy 21 and congenital heart disease have this defect. Specifically, 36% of patients with trisomy 21 have AVC defects.⁵²

The AVC defect represents the most common form of heart disease in trisomy 21,⁵³ followed by VSD, ASD, and then tetralogy of Fallot. Importantly, about 40% to 50% of patients with Down syndrome have congenital heart disease in general.^52,54 For trisomy 21, a CAVC defect is more common than an isolated primum ASD with cleft mitral valve, which only occurs in 3% to 25% of patients with isolated primum ASD and cleft mitral valve series.^13,52,55 A CAVC defect can also occur in the setting of tetralogy of Fallot, which is associated with a genetic abnormality about 88% of the time, 67.2% of which is trisomy 21.⁵⁶

Pathophysiology

As with the VSD and ASD, the shunt for a CAVC or isolated primum ASD is related to a drop in pulmonary vascular resistance. Thus, neonates may not have symptoms unless there are associated abnormalities. As the pulmonary vascular resistance falls, the infant can have symptoms of tachypnea, diaphoresis, and feeding difficulties, which can lead to failure to thrive. Of course, the VSD physiology of the AVC has a higher likelihood of causing symptoms than an isolated primum ASD with mitral valve cleft because the pulmonary arterial bed is under a pressure load and not just a volume load.

In addition to the left-to-right shunt, patients may have significant left atrioventricular, mitral valve, regurgitation, which elevates the left atrial pressure and can lead to worsening pulmonary venous congestion and respiratory symptoms. As with any of the left-to-right shunts, patients are at risk of recurrent respiratory infections if left untreated. Given that a large portion of patients with AVC have trisomy 21, it is important to note that children with trisomy 21 can have persistently elevated pulmonary vascular resistance in the first year of life compared to the normal patient population, which would make them potentially asymptomatic with no significant shunt.⁵⁷ However, children with trisomy 21 have a higher risk of fixed pulmonary vascular disease compared to children without trisomy 21, making the need for repair even greater.⁵⁷

Several important associated anomalies must be accounted for when treating neonates with AVC. If the canal is unbalanced, the atrioventricular valve favors 1 ventricle over the other, making the other somewhat hypoplastic. In some cases, the ventricles are so unbalanced that the hypoplastic chamber is inadequate to serve the needs of the systemic or pulmonary circulation. Most of the time, this is an unbalanced left ventricular AVC, which renders hypoplastic left heart syndrome. Coarctation of the aorta, atrioventricular valve regurgitation, LVOT obstruction, and tetralogy of Fallot (discussed previously) are other conditions associated with AVC defects. Rarer anomalies would include heterotaxy with either right or left atrial isomerism, double-orifice mitral valve,^{58, 59, 60, and 61} and cor triatriatum, a membrane that obstructs flow into the left ventricle.^62,63

Differential Diagnosis

The AVC defect usually presents with symptoms of a chronic left-to-right shunt just like the ASD or VSD; however, the patients may present sooner given the multiple levels of shunting and the association with other congenital heart disease noted previously. Thus, these patients can present with congestive heart failure, and other diseases that present in this manner must be excluded. Namely, noncardiac conditions would include sepsis, severe anemia, and hepatic and cerebral arteriovenous malformations, and an additional cardiac condition would be a patent ductus arteriosus or aortopulmonary window.

Diagnostic Tests

The ECG in patients with AVC defect have an unusual counterclockwise direction of the frontal electrical conduction vector, resulting in the classic northwestern QRS axis⁵² (Figure 19-5). Thus, a patient with this classic ECG finding along with the stigmata of trisomy 21 has an AVC defect until proven otherwise. Nonetheless, the echocardiogram can help determine the diagnosis more specifically. In addition, the associated lesions, such as balancing of the ventricles, valve regurgitation, left or ventricular outflow tract obstruction, and coarctation of the aorta, can be entertained. The typical appearance of the AVC is readily recognized from the 4-chamber view (Figure 19-4). The cardiac catheterization is reserved for those cases where the pulmonary vascular resistance is called into question if a child does not receive a repair early in infancy.

Management

Initial management in the past was PAB placement in infancy because of the poor results in infancy from CAVC defect repair.⁶⁴ Now, with improved techniques, surgery occurs predominantly in infancy without the need for a PAB. In the setting of a CAVC defect, there is no reason to wait beyond the 3-month age group to repair if there is a large VSD, which will only cause pulmonary vascular disease, especially in the large subgroup of trisomy 21 patients with pulmonary resistance issues from the start.⁵⁷ A primum ASD with a cleft mitral valve can be corrected later in life, and the timing of surgery is dependent on the institution’s practice. At the time of repair, the primum ASD and inlet VSD are repaired along with an associated lesion, with patching of the defects and repair of a cleft in the mitral valve. In the past, the CAVC defect was repaired late in infancy; however, improved morbidity and mortality associated with earlier repair supports the idea of not delaying surgical intervention.⁶⁵

Outcome and Follow-up

Without surgery, the survival for CAVC defect is 54% at 6 months of age and 35% at 12 months of age, 15% reach 24 months, and 4% reach 5 years of age⁶⁶; thus, surgery is recommended for the children at risk for florid heart failure as the pulmonary vascular resistance decreases and there are multiple shunts. Heart failure in combination and severe respiratory infections are the modes of death among patients with trisomy 21.⁵² However, there is no difference in outcomes comparing the patients with trisomy 21 with the nonsyndromic patients for AVC defect, ASD, or VSD lesions, which eventually lead to more children with trisomy 21 having congenital heart disease surgery.^53,67 The operative mortality has decreased significantly,^{68, 69, and 70} from 25% before 1976 to less than 4% after 1987. Complications after repair include death, 1.6%; postpericardiotomy syndrome, 13%; atrial arrhythmia, 3%; transient heart block, 1.6% to 3.5%; sternal wound infection, 0.5%; and left hemiparesis, 0.5%.^55,70 The 10-year survival is 98% in patients with AVC repair.⁵⁵ Some patients will require reintervention for mitral valve regurgitation (4%–7%)^70,71 or LVOT obstruction.

LEFT VENTRICULAR OUTFLOW TRACT ABNORMALITIES

Aortic Stenosis

The aortic valve in patients with aortic stenosis can have a variable morphology, appearing dysplastic, thickened, bicuspid, or hypoplastic. As a result of this aortic valve disease, neonates tend to present with variable degrees of obstruction; however, it is rare for infants to have significant aortic insufficiency without intervention. The presentation of aortic stenosis can be variable and depends on the degree of obstruction. In the most severe examples, the neonate is ductal dependent for systemic blood flow because of inadequate output from the left ventricle, and there is retrograde flow from the ductus arteriosus and aortic arch that feeds the brachiocephalic vessels and descending aorta. This clinical presentation is an example of critical aortic stenosis; however, much milder forms of aortic stenosis render the neonate asymptomatic.

Epidemiology

Aortic stenosis represents approximately 6% of all congenital heart disease and occurs in 6 of 10,000 live births.⁷² Twenty-five percent of cases will also have a fibrous or muscular subaortic stenosis associated with the aortic stenosis. Rarely, this condition can be associated with pulmonary stenosis, especially in the setting of congenital rubella syndrome.⁷³ Genetic syndromes are also known to be associated with aortic stenosis and include Turner, Goltz, Costello, and Williams syndrome. If these genetic syndromes are suspected, an evaluation for aortic stenosis and other congenital heart disease should be initiated.

Pathophysiology

As discussed, the presentation of aortic stenosis will vary depending on the degree of obstruction, which can be mild to severe. The aortic valve leaflets typically are bicuspid and thickened with a decrease in cross-sectional area and can have associated supravalvar or subvalvar narrowing. Because of the obstruction to the aortic valve, the left ventricle can be hypertrophied in accordance with the degree of stenosis. In some cases with severe obstruction, the left ventricle begins to fail, resulting in a dilated ventricle with diminished systolic function. As a result of the high afterload, there can be endocardial fibroelastosis, which can impair both systolic and diastolic function of the left ventricle. With impaired diastolic function, the left ventricle fails to relax, resulting in high end-diastolic pressure and thus high left atrial and pulmonary arterial pressure from the back pressure.

The other common associated lesions include patent ductus arteriosus, coarctation of the aorta, VSD, ASD, mitral stenosis, and Shone’s complex.^73,74 Shone’s complex is a heart condition with multiple left heart obstruction lesions that traditionally include parachute mitral valve (single papillary muscle), supravalvar mitral ring, congenital mitral stenosis, subaortic stenosis (and valvar aortic stenosis), and coarctation of the aorta. Eight percent of patients with aortic stenosis have Shone’s complex.⁷⁵ Often with Shone’s complex, the left ventricle is deemed inadequate to handle the work of the systemic circulation, and the neonate must undergo a Norwood procedure for hypoplastic left heart syndrome.

Approximately 63% of the time, however, there is no associated pathology. As a result of the high left atrial pressure from decreased relaxation, there can be associated pulmonary hypertension 7% of the time.⁷⁵

Neonates with aortic stenosis will present with the symptoms of congestive heart failure only if there is a significant amount of obstruction across the valve, and they can have tachypnea, diaphoresis, feeding difficulties, and failure to thrive. On physical examination, there should be a systolic ejection murmur that radiates to the neck with or without an associated thrill. A click should accompany the murmur because there is valvar involvement while the apical impulse will be increased.^73,76 Patients with even mild aortic stenosis should have the murmur findings but would probably be asymptomatic; however, patients with significant obstruction may also have a narrow pulse pressure.⁷³

Differential Diagnosis

Neonates with critical aortic stenosis tend to be very ill and present in shock unless the ductus arteriosus is open and there is retrograde flow from the descending aorta to the ascending aorta. Thus, any lesion in the neonate that can cause symptoms of shock should be present in the differential diagnosis, such as sepsis, severe anemia, or hypovolemic shock from blood loss. In addition, any cardiac condition that is ductal dependent for systemic blood flow can present similarly, such as coarctation of the aorta, hypoplastic left heart syndrome, or aortic arch interruption.

The neonate with aortic stenosis who is not ductal dependent for systemic blood flow may still have severe aortic stenosis and would present with a heart murmur. The location of the heart murmur should be at the right upper sternal border with radiation to the neck; however, this distinction may be difficult in the neonate with faster heart rates and smaller chests. Thus, pulmonary stenosis may be confused with the diagnosis of aortic stenosis. Also, valvar aortic stenosis would present with the same type of murmur as supravalvar aortic stenosis or subvalvar aortic stenosis given the location of turbulent blood flow. However, valvar aortic stenosis is accompanied by a click, which should be absent in the last 2.

Diagnostic Tests

On ECG, the neonate may have ECG features of left ventricular hypertrophy with a strain pattern. This feature on the ECG would be unusual because most neonates have right-dominant forces. A chest x-ray in a patient with severe aortic stenosis would have a cardiothoracic ratio greater than 50% and would not necessarily have poststenotic dilation of the ascending aorta.^72,73 Again, both of these tests would be nonspecific, and the echocardiogram would provide more definitive information, such as aortic valve thickening, bicuspid aortic valve, patent ductus arteriosus, aortic arch issues, or coarctation (Figure 19-6). Some features of the aortic valve, mitral valve, endocardial fibrosis, and left ventricle size help determine if the neonate has merely severe aortic stenosis or features of hypoplastic left heart syndrome.^77,78 In addition, Doppler techniques define the aortic valve gradient, which aids in the management of this lesion.

Management

The mainstay of treatment of either critical or severe aortic stenosis with a normal-size left ventricle and no significant mitral valve disease is balloon aortic valvuloplasty as opposed to surgical valvotomy. Aortic valve stenosis is the most common type of LVOT obstruction, and balloon valvuloplasty only works at the valvar level.⁷⁹ The efficacy and mortality rate are similar to surgical techniques without the need of cardiopulmonary bypass and sternotomy.⁸⁰ The aortic valve gradient improves to acceptable levels without severe aortic insufficiency in most cases. Critical aortic stenosis is defined as enough left ventricular outflow obstruction such that the neonate is ductal dependent for systemic blood flow, an indication for balloon valvuloplasty. Severe aortic stenosis presentation and management strategies, however, vary. Nonetheless, the guidelines for valvuloplasty in severe aortic stenosis are a peak systolic gradient by echocardiographic Doppler techniques of 75 mm Hg, presence of strain on ECG, syncope, angina pectoris, fatigue with exercise, or severe left ventricular dysfunction.⁸¹ Thus, balloon aortic valvuloplasty has become a widely accepted modality for the initial treatment of severe aortic stenosis; however, more complicated cases may require direct visualization with surgery.^{82, 83, 84, 85, 86, and 87}

A major complication from balloon valvuloplasty is aortic wall injury, specifically creation of an intimal flap, which is an underrecognized complication of neonatal balloon aortic valvuloplasty, occurring in 15% of cases even in the recent era.⁸⁸ Repeat balloon dilation may be necessary, especially in the neonatal period with the risk of increasing aortic regurgitation.

Outcome and Follow-up

In cases of aortic stenosis for which there is heart failure in patients under the age of 18 months, the natural history is that 72% of these patients die.⁷³ Untreated severe aortic stenosis also has a poor prognosis.⁷⁶ Mild aortic stenosis still needs follow-up because only 20% of patients with mild aortic valve stenosis remain with mild symptoms into adulthood and may likely need some form of intervention.⁸⁹ In general, neonatal critical aortic stenosis, which occurs 10% of the time, tends to have a worse prognosis.⁹⁰

Other factors also influence prognosis and increase mortality in severe aortic stenosis and include small aortic annulus, depressed systolic function, low aortic valve gradient, and endocardial fibroelastosis.⁸⁶ In addition, the size of the aortic valve and mitral valve calls into question the possibility of whether the left ventricle is suitable as a systemic pump given the relatively smaller size. Thus, some studies have investigated the use of certain morphologic characteristics of the left heart structures to determine if a single ventricle or biventricular physiology is superior.^77,91

In those patients who are deemed to be amenable to an aortic balloon valvuloplasty, the prognosis is good, with about two-thirds of the patients needing no further surgical intervention 10 years after intervention.⁸¹ Mortality is predominantly limited to the neonatal period around the time of aortic valve intervention. Beyond this period, mortality is nearly absent; however, many may require reintervention at some point for either recurrent aortic stenosis or aortic insufficiency from the balloon valvuloplasty.⁹² The rate of progression of the aortic valve gradient tends to be slow over time.⁹² Sudden death after balloon aortic valvuloplasty is extremely low, at 18 of 100,000 patient-years in children over 4 years of age.⁹³

Coarctation of the Aorta

The coarctation of the aorta represents a narrowing in the aortic arch, typically beyond the left subclavian artery near the ductus arteriosus. Usually, there is a localized, narrow, constrictive lesion that appears as an infolding of the aortic media into the lumen.⁹⁴ As a result of this obstruction, neonates can present with shock from the lack of blood flow into the descending aorta to just a murmur with some systemic hypertension. Diminished lower-extremity pulses are the hallmark of this lesion and are the best, most reliable method of detecting it. Given that patients with aortic coarctation can present in shock, the clinician managing neonates should always attempt to detect this lesion.

Epidemiology

Coarctation is 1 of the 4 most common cardiac malformations, representing 14.8% of cardiac lesions.⁹⁵ As a frame of reference, VSD occurs 18% and transposition occurs 16% of the time in the same series.⁹⁵ Approximately 50% of deaths from neonatal coarctation occur after 7 days of life, and it is rare the first 2 days of life.⁹⁵ Noncardiac anomalies associated coarctation which include urinary tract malformations and tracheoesophageal fistula. The natural history of aortic coarctation is that 60% will die during infancy, with only 1 additional cardiac lesion, while 76% die if there are multiple cardiac defects.⁹⁴

Simple coarctation occurs 61% of the time if there is no associated lesion. Complex coarctation with a VSD occurs 33% of the time; the remaining 6% of coarctation lesions are more complicated lesions.⁹⁶ One of the more common genetic syndromes associated with aortic coarctation is Turner syndrome.⁹⁷

Pathophysiology

The primary issue in neonates with critical coarctation of the aorta is the ventricular dysfunction and shock that accompany the lack of cardiac output distal to the obstruction, leading to metabolic acidosis. Neonates do not present with symptoms usually until after 48 hours of life because the ductus arteriosus is protective and allows for distal perfusion.⁹⁵ The ductus arteriosus, with the blood flow from the right ventricle, usually supplies the descending aorta distal to the obstruction, and when the ductus arteriosus closes, the obstruction to the aortic arch is unmasked. Another mechanism of obstruction is where the aortic arch has an associated sling of ductal tissue that forms a ring around the aorta.⁹⁸ When the ductus arteriosus closes, the aortic arch becomes obstructed.

In 1 series, all infants with coarctation develop signs of congestive heart failure by 6 months of age; however, there are other series in which patients do not present until later with systemic hypertension.⁹⁴ Usually, in addition to the aortic isthmus obstruction, there is tubular hypoplasia of the distal transverse arch in a majority of neonatal coarctation.^94,98 Rarer forms of coarctation can occur between the left common carotid and left subclavian artery as well as the abdominal aorta.⁹⁹ The former will give rise to discrepant arm blood pressures, while an abdominal aorta coarctation will appear similar to the standard isthmus coarctation on physical examination.

Complex coarctation can occur with a VSD, ASD, or aortic stenosis.⁹⁴ Often, the aortic valve will be malformed, with a dysplastic or bicuspid aortic valve.⁹⁹ The VSD with aortic coarctation is often a posterior malalignment type, which can lead to subaortic obstruction and a somewhat smaller aortic valve. Coarctation can also occur with AVC defects, as previously described in this chapter.⁹⁹ Other reported associations include double-outlet right ventricle and complete transposition.¹⁰⁰

Bicuspid aortic valve with fusion of the left and right coronary cusps is associated with coarctation, while those with right noncoronary fusion are associated with severe aortic stenosis and valve dysfunction.¹⁰¹ Both forms of bicuspid aortic valve are associated with aortic root dilation, but this is more common in the latter form.¹⁰¹ Bicuspid aortic valve with coarctation tends to have less aortic root dilation over time compared to isolated bicuspid aortic valve.¹⁰²

Neonates who present with coarctation of the aorta tend to have symptoms of tachypnea, respiratory distress, and feeding intolerance.^{103, 104, and 105} As mentioned, coarctation of the aorta symptoms develop usually after the ductus arteriosus begins to close. With the development of symptoms, the pulses will be diminished or absent on physical examination. There will be radial-to-femoral delay in pulses. In critical coarctation of the aorta, the lower-extremity pulses will have lower oxygen saturations compared to upper-extremity pulses because the less-oxygenated blood of the right ventricle supplies the descending aorta. However, this may not be appreciable in the setting of a VSD because there can be left-to-right shunting that increases the ductal oxygen saturations. Upper- and lower-extremity blood pressure should be obtained whenever coarctation of the aorta is suspected to confirm a decrease in the lower-extremity blood pressure.

For neonates with coarctation that is not severe or critical, the presenting sign may be merely diminished pulses and upper-extremity hypertension. Upper- and lower-extremity blood pressure would also be discrepant in milder forms of coarctation.

Differential Diagnosis

Because shock and metabolic acidosis may be the presenting symptoms of coarctation, any disease process that can give those types of symptoms ought to be ruled out, such as sepsis, severe anemia, hypovolemic shock from blood loss, or other metabolic processes. Again, neonates with hypoplastic left heart syndrome and critical coarctation will also present in shock as a result of ductal closure and should be included in the differential diagnosis as well.

Diagnostic Tests

The physical examination is the single most important diagnostic test for coarctation with the presentation of absent or weak pulses. An ECG may demonstrate right axis deviation with right ventricular hypertrophy in 63% to 73% of cases⁹⁴; however, this test is nonspecific. Echocardiography accurately detects coarctation of the aorta using suprasternal notch imaging⁹⁹; however, the presence of a bicuspid aortic valve or VSD should provide some clues for coarctation as well. Computed tomographic (CT) angiography can provide excellent visualization of the aortic arch and coarctation when ultrasound imaging is deficient or the arch anatomy is complicated (Figure 19-7). With modern fetal echocardiography, the prenatal diagnosis of coarctation is feasible; however, the normal presence of the ductus arteriosus makes the diagnosis difficult.⁹⁶

Management

The initial management strategy in the most severe forms of coarctation is to reverse the congestive heart failure and reverse metabolic acidosis, especially when neonates present in shock. Mechanical ventilation aids with removing the work of breathing. Most important, prostaglandin E_l (PGE₁) should be used to dilate the ductus arteriosus, improve systemic output, and increase renal blood flow and urine output. Thus, as the ductus arteriosus opens, the ductal sling around the aorta opens, and the right ventricle can help with supplying descending aorta flow with right-to-left ductal shunting. Surgery is used in the neonatal period to avoid systemic hypertension even with milder forms of coarctation. Unrepaired, there can also be left ventricular failure, myocardial fibrosis, or death. If the ductus arteriosus does not open in critical coarctation despite high-dose PGE₁ therapy, urgent surgery will become necessary because there is a failure in medical management. In neonates who present with shock and the ductus opens, time should be provided to allow for end-organ recovery from the shock.

The surgical treatment of coarctation has evolved from the subclavian flap to the end-to-end anastomosis and synthetic graft to fix coarctation.^106,107 Most centers elect to perform an extended end-end or an end-to-side anastomosis.^108,109 With modern techniques, the recoarctation rate is much less at less than 6% (Figure 19-8).^{108, 109, and 110}

Balloon angioplasty of native coarctation is not a great option because of the residual coarctation, greater than 20 mm Hg in 38% of patients.¹¹¹ In addition, this technique does not address distal hypoplasia of the arch, and there can be an intimal tear in 2.5%, resulting in aneurysm formation.^{111, 112, and 113} After surgical repair, echocardiogram Doppler techniques along with 4-limb blood pressure measurements can be used to assess the surgical repair.

Outcome and Follow-up

Medical management alone is inadequate, and there is no survival for critical coarctation with additional defects.⁹⁴ However, even with critically ill patients treated with PGE₁, mechanical ventilation, and catecholamines, at least 84% survive to at least 24 months.¹¹⁴

After surgical repair, many complications may arise and include spinal cord injury, left hemidiaphragm paralysis, left vocal cord paralysis, weak left radial pulse (subclavian flap-type repair), scoliosis about 3 years after surgery,¹¹⁵ and residual systemic hypertension.^103,116,117 Persistent residual systemic hypertension is highly unlikely for neonates.^103,116 The mortality rate is low even when the neonate presents with shock and severe metabolic acidosis and is typically less than 5% in more recent series.^109,118,119

Aortic Arch Interruption

The aortic arch interruption lesion, like the double-outlet right ventricle, tetralogy of Fallot, or transposition of the great vessels, is thought of as a conotruncal abnormality. The aortic arch can be completely interrupted in 3 primary locations between the left subclavian artery and the descending aorta (type A), the left common carotid artery and the left subclavian artery (type B), and the right innominate artery and the left common carotid artery (Figure 19-9). Type A interruption could represent the most severe form of aortic coarctation given its location. In coarctation, there is some prograde flow across the narrowing, and in interruption, there is no communication between the vessels. Because there is no communication between the proximal and distal arch, a patent ductus arteriosus must be present to supply the distal perfusion. If the ductus arteriosus were to close in neonates with aortic arch interruption, profound shock and metabolic acidosis would ensue. The lower-extremity oxygen saturation tends to be decreased when compared to the right upper extremity because deoxygenated blood arises from the right ventricle, which pumps to the ductus arteriosus and feeds the distal arch.

Epidemiology

Type B aortic arch interruption between the left common carotid and left subclavian artery is the most common form of arch interruption at 67%.¹²⁰ Type A is less common at 25%, and type C is rare at 8%.¹²⁰ The advent of PGE₁ has increased survival because lower-extremity perfusion is dependent on patency of the ductus arteriosus¹²¹; otherwise, surgery to repair the arch must take place before the ductus arteriosus closes. Like all conotruncal abnormalities, 22q11 microdeletion should always be considered and is present in 82% of type B but is less common in type A interruption.^122,123

Pathophysiology

Embryologically, involution of the fourth arch in utero, which represents the communication between the common carotid and subclavian artery on either the left or the right depending on the arch sidedness, is the mechanism of type B interruption.¹²⁴ Failure of the left or right dorsal aorta beyond the fourth arch creates a type A interruption, while type C is caused by failure of the third and fourth arches.

Neonates with arch interruption, regardless of the type, will present with early heart failure, weak lower-extremity pulses, strong carotid pulses, and differential cyanosis from the desaturated blood exiting the right ventricle and supplying the lower extremities via a ductus arteriosus. Often with arch interruption, the right subclavian artery can arise anomalously and also be the ductus arteriosus, resulting in lower oxygen saturation in all limbs compared to the cerebral saturation.

There is almost always a ductus arteriosus to supply the lower-extremity perfusion; however, there are case reports of collateral flow from the vertebral arteries and thyrocervical trunk.¹²⁵ In 94% of cases, there is a large, posterior malalignment-type VSD¹²⁶; there are also case reports of direct connections between the aorta and pulmonary artery, also known as an aortopulmonary window, and no VSD.^{127, 128, and 129} Most important, as a result of a narrow LVOT, the aortic valve can be malformed, bicuspid, and hypoplastic.¹³⁰ This outflow tract pathology may lead to severe subaortic or aortic stenosis, which can alter the management of these patients significantly. An interrupted aortic arch is also associated with mitral stenosis/atresia, persistent truncus arteriosus, or double-outlet right ventricle. The mortality rate for arch interruption increases significantly when associated with persistent truncus arteriosus.¹³¹

Differential Diagnosis

Patients with arch interruption, if left alone, will present with shock, metabolic acidosis, and diminished pulses. As mentioned regarding aortic stenosis or coarctation of the aorta, other lesions that can cause shock in the neonate must be excluded. Interrupted aortic arch has an interesting diagnostic feature of differential cyanosis as well; however, this is not necessarily unique because severe coarctation that is nearly interrupted and severe pulmonary hypertension may also show decreased lower-extremity saturation. As mentioned, the differential cyanosis may not be appreciable if the right subclavian artery also arises below the interruption and all extremities are fed by the ductus arteriosus. In addition, because there is a VSD, the left-to-right shunt as the pulmonary vascular resistance drops in the neonate may cause the lower-extremity saturation to increase, minimizing any differential cyanosis.

Diagnostic Tests

An ECG may show left or right ventricular hypertrophy; the chest x-ray may demonstrate cardiomegaly with increased pulmonary vascular markings. Both findings would be nonspecific and not diagnostic. Echocardiography is the mainstay of diagnosis even in fetal life.¹³² The arch interruption level can be defined as well as the location of the VSD. The LVOT can be visualized to ascertain any obstruction or hypoplasia.

Management

Once the diagnosis of aortic arch obstruction has been identified, PGE₁ can be initiated to ensure adequate systemic perfusion. PGE₁ therapy can be accompanied by fever, irritability, hypotension, or apnea. Thus, the clinician should search for these side effects. Given the presence of a VSD and runoff diastolic flow into the branch pulmonary arteries from the ductus arteriosus, neonates can quickly develop pulmonary edema. Therefore, surgical intervention should not be delayed too long because of this complication.

The surgical procedure involves an aortic arch reconstruction and repairing any VSD or subaortic obstruction.^133,134 If the LVOT is deemed to be too small, the left ventricle can often be baffled to the pulmonary valve to relieve obstruction, and a conduit from the right ventricle to pulmonary arteries would function as the right ventricular outflow. This procedure with the arch reconstruction is not as ideal as repairing the arch and closing the VSD because the conduit will not grow with the neonate and would need to be replaced in the future.

Outcome and Follow-up

Untreated, 80% of infants with aortic arch interruption will die in the first month of life.¹³⁵ If a child survives the infancy period because of a ductus arteriosus, uncorrected Eisenmenger syndrome is the natural outcome because of unrestrictive shunting through a VSD and ductus arteriosus.¹³⁶ Interrupted aortic arch with subaortic obstruction is a more complicated lesion because of residual subaortic obstruction or the complex baffling the left ventricular flow to the pulmonary valve. In fact, this combination of defects is met with 13% mortality and risk for need of reoperation.^134,137 However, with modern techniques and the advent of PGE₁, the operative mortality of all aortic arch interruption has decreased dramatically from 65% to less than 5%.^{138, 139, and 140} Most heart centers now advocate for a single-stage repair approach.^140,141

RIGHT VENTRICULAR OUTFLOW TRACT ABNORMALITY

Pulmonary Stenosis

As with aortic stenosis, pulmonary stenosis is a result of a malformed, dysplastic, thickened, or bicuspid pulmonary valve. The clinical manifestations vary significantly from just a heart murmur to critical pulmonary stenosis by which the neonate is dependent on a patent ductus arteriosus for pulmonary blood flow. Management strategies will depend mostly on the degree of obstruction across the right ventricular outflow tract.

Epidemiology

The frequency of pulmonary stenosis is similar to that of aortic stenosis, occurring in 6 of 10,000 live births and 6 of 100 live births with congenital heart disease.⁷² In the past, there was a high association with congenital rubella syndrome, for which there can be multiple levels of obstruction at the pulmonary valve, main pulmonary artery, or the branches.¹⁴² Genetic syndromes are also heavily implicated with pulmonary stenosis, especially Williams and Noonan syndromes.¹⁴³ The valve is highly dysplastic when there is an associated genetic condition.

Pathophysiology

When there is severe obstruction as a result of pulmonary stenosis, the majority of neonates will have some degree of cyanosis, and some will have right ventricular failure as a result of the high afterload on the myocardium.¹⁴⁴ Because of severely elevated right ventricular end-diastolic pressure from the pulmonary stenosis and sometimes somewhat hypoplastic tricuspid valves, neonates will frequently shunt right to left across a patent foramen ovale, which (although it causes cyanosis) also allows the left ventricle to fill. Some neonates will have a true secundum ASD in association with pulmonary valve stenosis. As a result of pulmonary stenosis, older children may have dilation of the main pulmonary artery; however, this is unlikely in a neonate or infant.¹⁴⁴

The pulmonary valve is supposed to have 3 thin mobile leaflets with excellent excursion; however, with pulmonary stenosis, the leaflets may dome in systole with fusion of the cusps or have a pinhole orifice, resulting in right ventricular hypertrophy and near obliteration of the cavity.¹⁴⁵ As a result of the pulmonary stenosis, the infundibulum will also hypertrophy, which can lead to subpulmonary valve obstruction as well. In fact, the most severe form of pulmonary stenosis would be atresia of the pulmonary valve with an intact ventricular septum. This particular lesion can have a similar presentation to critical pulmonary stenosis with a pinhole orifice. Despite all of the pathology associated with the pulmonary valve, it is rare to have significant pulmonary insufficiency in the neonatal period.⁷²

Neonates will present quickly with dyspnea, feeding difficulties, hepatomegaly, and a harsh systolic ejection-type murmur with a thrill if there is severe pulmonary stenosis.¹⁴⁵ In fact, the right ventricular pressure can be above systemic levels as a result of pulmonary stenosis. Despite the high afterload on the right ventricle, rarely do newborns or infants present with edema.¹⁴⁵ Neonates with mild-to-moderate pulmonary stenosis will in all likelihood be relatively asymptomatic.⁷²

Differential Diagnosis

The murmur of aortic stenosis may sound similar to that of pulmonary stenosis; however, in the latter there is radiation of the murmur to the back. If there is significant obstruction, the clinician must differentiate this lesion from cyanotic congenital heart disease, which is discussed in another chapter. If there is significant obstruction, the tricuspid valve regurgitation may also be audible and would be holosystolic. Given that there can be a paucity of pulmonary vascular markings and an increase in right ventricular forces in neonates with severe pulmonary stenosis, this lesion must be differentiated from pulmonary hypertension.

Diagnostic Tests

The classic ECG findings in neonates with severe pulmonary stenosis would include right atrial enlargement and right ventricular hypertrophy with voltages exceeding 20 mm; however, the ECG can be normal in milder forms of the disease.^144,145 As discussed previously, the chest x-ray can demonstrate cardiomegaly with decreased pulmonary vascular markings; however, the enlargement of the main pulmonary artery from poststenotic dilation may not be apparent until after infancy.¹⁴⁴

The echocardiogram is the mainstay for the diagnosis, can provide accurate Doppler-derived pulmonary stenosis gradients, and can provide an anatomic view of the pulmonary valve.¹⁴⁶ The gradient by echo correlates well with the cardiac catheterization-derived pressure gradient¹⁴⁶ (r = 0.98). Of note, careful attention should be placed on the pulmonary and tricuspid valve annulus size to see if surgical or cardiac catheterization interventions would be successful.

Management

Even in the early surgical era, the mortality rate for pulmonary valve repair was low at 4%.¹⁴⁴ Management has been altered, however, with the advent of advanced interventional cardiac techniques (Figure 19-10). Pulmonary valvuloplasty has become the standard of care for patients with critical pulmonary stenosis, with great short- and long-term results. Surgery should be reserved for those patients with a hypoplastic tricuspid valve and right ventricle.^{147, 148, 149, 150, 151, 152, and 153} In these cases with hypoplastic right ventricle associated with severe pulmonary stenosis, an aortopulmonary shunt may be necessary with a single- or “1.5-ventricle” repair strategy in the future.¹⁵⁴

The advantage of balloon intervention is that there is no need for cardiopulmonary bypass, blood products, and sternotomy. Results are variable when the pulmonary valve is very dysplastic and thickened, however.^148,149 The mechanism by which balloon valvuloplasty works is by splitting the commissural fusion of the pulmonary valve and thereby relieving the stenosis.¹⁴⁹

Outcome and Follow-up

Survival has improved with the advent of PGE₁ as a part of therapy to augment pulmonary blood flow in cases of critical pulmonary stenosis. Patients with critical pulmonary stenosis have not done well in the past prior to the use of PGE₁ therapy.¹⁵⁵ Severe pulmonary stenosis is a grave condition, leading to death if no intervention is conducted early in life.^144,145

In 1 large series of 68 patients with pulmonary stenosis but no congestive heart failure or cyanosis, pulmonary stenosis was unlikely to progress, and the patient generally had a good prognosis.¹⁵⁶ If pulmonary stenosis remains mild after 1 year of life, it is unlikely to progress, while moderate-to-severe pulmonary stenosis can worsen in severity.^{156, 157, and 158} At older ages, it is unlikely for mild pulmonary stenosis to progress. In fact, there are cases of a natural cure for mild pulmonary stenosis by which the gradient across the valve goes away.¹⁵⁹

After pulmonary valvuloplasty, there might still be right-to-left shunting across an atrial communication despite adequate relief of the pulmonary outflow obstruction because the right ventricular end-diastolic pressure might be high from impaired right ventricular compliance.¹⁵⁵ However, as the obstruction is most often relieved with adequate balloon dilation, the right ventricle relaxes over time, and the cyanosis improves.

REFERENCES

EPIDEMIOLOGY

Incidence and Definitions

Hypotension is a common problem in the neonatal intensive care unit (NICU).¹ More than half of neonates admitted to the NICU also carry the diagnosis of hypotension. Although the incidence is higher with lower gestational age at birth, the exact incidence is not known. This is primarily because of the lack of consensus on what constitutes hypotension.² Indeed, there are many ways to define neonatal hypotension, and the differences among the definitions obviously affect the reported incidence of hypotension and the decision to treat the condition.^3,4 As the ultimate goal is to ensure that oxygen delivery matches tissue oxygen demand in all organs, hypotension best can be defined based on physiologic principles, that is, by assessing the effects of decreased perfusion pressure on organ blood flow and oxygen delivery. However, because in the first, “compensated” phase of shock, vital organ (brain, myocardium, adrenal glands) blood flow and blood pressure (BP) are maintained by the neuroendocrine mechanism-driven redistribution of blood flow from nonvital organs, hypotension only presents when shock enters its second, “uncompensated” phase and vital organ blood flow also declines. Therefore, hypotension can be best defined as the BP below which vital organ (eg, brain) blood flow autoregulation is lost and cerebral blood flow (CBF) starts decreasing in proportion to the decrease in BP (the so-called autoregulatory threshold of hypotension; Figure 20-1).⁵ On further decrease in BP and oxygen delivery, cellular function cannot be appropriately maintained, but structural integrity is not yet significantly affected (the so-called functional threshold of hypotension; Figure 20-1).⁵ Finally, on further decline in BP and oxygen delivery, structural integrity of tissues becomes affected, resulting in permanent organ damage (the so-called ischemic threshold of hypotension; Figure 20-1).⁵ Unfortunately, there are few data on the cutoff values, and because the capacity of the cardiovascular and neuroendocrine systems to appropriately compensate is affected by gestational and postnatal age as well as the underlying pathophysiology, these values likely vary in the individual patient and even for the same patient at different times.

On the other hand, the clinical definition of hypotension is straightforward because it is absolutely arbitrary. In clinical practice, hypotension in very low birth weight (VLBW) infants has been defined as a mean BP below the gestational age in numerical value⁵ as this number is close to the 5th (or 10th) percentile of the population-based mean normative BP values for gestational age for the given patient population.⁶ A number of researchers and clinicians also define hypotension in VLBW neonates during the first postnatal days as a mean BP below 28 to 30 mm Hg.^{7, 8, and 9} The last definition of hypotension is based on findings suggesting that the lower elbow of the CBF autoregulatory curve is around these values in VLBW neonates (Figure 20-1).^{9, 10, and 11}

More recently, likely because of the lack of a clinically relevant (ie, mortality and long-term outcome-based) definition of hypotension, the idea of “permissive hypotension” has been introduced in the literature.¹² The permissive hypotension strategy calls for disregard of BP in the clinical assessment of the patient’s cardiovascular status. Instead, the strategy calls for focusing only on assessment of adequacy of organ perfusion by evaluating clinical and laboratory indicators of tissue perfusion. Although BP is the dependent variable among the factors defining macrohemodynamics (see the section on pathophysiology), appropriate perfusion pressure is absolutely necessary to drive blood flow through the entire circulatory system (macro- and microcirculations). Therefore, the idea to discard BP as one of the hemodynamic factors in the assessment of the cardiovascular status essentially disregards the basic principles of cardiovascular physiology.

In addition, the clinical and laboratory indicators of adequacy of perfusion are either unreliable or delayed in presentation, rendering them less useful.¹³ However, as none of the definitions of hypotension in itself has been shown to be associated with improved outcomes when “hypotension” is treated, the BP values are indeed arbitrarily used to trigger initiation of treatment. Finally, to make matters worse (ie, even more complex), having a BP above the cutoff value also does not ensure adequacy of perfusion in part because patients first enter the compensated phase of shock where BP remains within the “normal range” (see also the BP and blood flow interaction discussion that follows).

Figure 20-2 shows an example of statistically defined normal BP.¹⁴ The lines represent the lower limit of the 80% confidence interval of BP for each gestational age group during the first 3 days of postnatal life. Therefore, 90% of neonates will have a mean BP value at or above this lower limit. Although adequacy of organ perfusion cannot be deduced from these data or similar, statistically derived normative values, the graph clearly demonstrates that BP is directly related to both gestational and postnatal age and therefore can be used as a guideline in the initial assessment of neonates with suspected hemodynamic instability.¹⁵

Risk Factors

Certain neonatal patient populations are more likely to develop hypotension and circulatory failure and suffer from the complications associated with inadequate tissue perfusion. Prematurity, lack of exposure to antenatal steroids, chorioamnionitis, perinatal infection, perinatal depression, pre- and postnatal exposure to certain medications, respiratory distress syndrome, and persistent pulmonary hypertension are among the risk factors for developing hypotension. There are many reasons that the neonate, especially the preterm neonate, is vulnerable to the hemodynamic effects of hypotension. The immaturity of organ systems in general and the brain in particular predisposes the preterm infant to organ damage. The narrow BP range of CBF autoregulation¹⁰ and its attenuation or complete loss in situations that are all but too common (eg, hypercarbia and hypotension) in the preterm neonate can adversely affect CBF and contribute to the development of brain injury.

Recently, we have proposed that vital organ assignment might be developmentally regulated, and that in extremely preterm infants the forebrain is a nonvital organ during the first 24 to 48 hours following delivery.¹⁶ Indirect evidence in preterm neonates and studies in developing animals support this hypothesis and demonstrate that, unlike in the hindbrain, vessels in the forebrain constrict in response to hypoxia or hypoperfusion.^17,18

PATHOPHYSIOLOGY

Careful attention to the principles of cardiovascular physiology and the interaction between BP and systemic and organ blood flow are important in understanding the pathophysiology of hypotension and shock (Figure 20-3).^19,20 According to Poiseuille’s law, flow is directly related to the pressure gradient and diameter of the vessel and inversely related to the length of the vessel and the viscosity of the fluid. Thus, pressure is the driving force behind moving blood through the vasculature. In clinical practice, Ohm’s law is used to describe the interaction between BP, blood flow (cardiac output, CO), and systemic vascular resistance (SVR): BP ∝ SVR × CO. Accordingly, physiologic and pathologic changes in the 2 relatively independent parameters (CO and SVR) determine the dependent parameter, BP. Considering this interaction, BP would not change if, for example, CO drops by 50% and SVR doubles. This also illustrates the fact that BP is one of the principle parameters among the hemodynamic indicators of perfusion that should be monitored.

In defining the pathophysiology of hypotension and cardiovascular compromise, it is useful to evaluate the components of SVR and CO, the two so-called independent variables (Figure 20-4). Disturbances in regulation of or pathologic alterations in vascular tone, heart rate, preload, contractility, or afterload can all lead to hypotension and cardiovascular compromise. Therefore, based on the underlying pathophysiology, we can identify the primary etiology for hypotension, including disturbances of vascular tone (vasodilation and vasoconstriction); arrhythmia; conditions primarily affecting preload (hypovolemia and diastolic dysfunction); and contractility (myocardial injury or hyperdynamic myocardium) as well as increased or decreased afterload (Table 20-1). Among the underlying causes of hypotension and shock, vasodilation and poor contractility are the most common etiological factors in neonates, especially in preterm infants.

Disturbances of Vascular Tone

Regulation of vascular smooth muscle tone is complex and involves a delicate balance between vasodilator and vasoconstrictor signals controlled by the autonomic nervous system as well as endocrine mechanisms and paracrine and local vasoactive factors. The most important endocrine, paracrine, and local regulators of vascular tone include nitric oxide, eicosanoids, vasopressin, catecholamines, renin-angiotensin system, and endothelin. Some of the factors, such as locally generated nitric oxide and vasodilatory eicosanoids, are increased in septic shock and generalized inflammatory diseases and are considered the main cause of the associated poor vascular tone and vasodilatory shock in these conditions. Given the high incidence of clinical conditions with elevated inflammatory mediators such as chorioamnionitis, respiratory distress syndrome, necrotizing enterocolitis, inappropriate oxygen exposure, and immaturity of the autonomic nervous system, especially in the very preterm neonate, it is not surprising that vasodilation plays a significant role in the pathogenesis of circulatory failure in these patients.

Disturbances in Heart Rate and Rhythm

Although transient sinus bradycardia and tachycardia are common in neonates, it is the more sustained problems with cardiac rhythm that can lead to hypotension and circulatory failure. Among arrhythmias potentially leading to circulatory compromise, supraventricular tachycardia and hyperkalemia-related tachyarrhythmia are the most frequently occurring clinical presentations.

Disturbances of Preload

In general, conditions that decrease preload by resulting in absolute hypovolemia, such as acute blood loss, are rare. Moreover, the lack of evidence of a well-defined relationship between blood volume and BP in preterm neonates further supports the generally accepted notion that absolute hypovolemia is not a common cause of hypotension in the neonatal period.^{21, 22, and 23} However, it must be noted that these studies^{21, 22, and 23} were performed on more mature preterm neonates. Moreover, the recent findings of improved hemodynamics associated with delayed cord clamping suggest that some degree of decreased circulating blood volume is indeed not uncommon, especially in the very preterm neonate, and that having a higher absolute circulatory volume at birth might be beneficial.^24,25 Of course, there may be additional mechanisms in play contributing to the improved hemodynamics seen following delayed cord clamping. For example, a more gradual increase in afterload when cord clamping is delayed rather than the abrupt afterload increase associated with the immediate clamping of the cord might allow for improved adaptation of the immature myocardium of the very preterm neonate.

On the other hand, reduced preload, despite the absence of significant absolute hypovolemia, is not uncommon. High intrathoracic pressure due to an inappropriately high mean airway pressure or a tension pneumothorax as well as the presence of a pericardial effusion can significantly decrease CO by decreasing venous return. Furthermore, although its role in the pathogenesis of hypotension has not been adequately studied, the decreased compliance of the immature myocardium could also limit the filling of the heart. Finally, significant diastolic dysfunction can contribute to decreased filling and thus decreased preload in patients with hypertrophic cardiomyopathy or in patients treated with inappropriately high doses of inotropes, especially dobutamine. Patients with hypertrophic cardiomyopathy are usually born to mothers with diabetes, and the small ventricular cavity and hyperdynamic myocardium result in significant reductions in preload.

Disturbances of Myocardial Contractility

Because of both structural and functional immaturity, the myocardium of the neonate is more prone to decreased contractility (Figure 20-5).²⁶ Myocardial dysfunction has been documented in about one-third to a half of very preterm infants presenting with hypotension or poor perfusion.^27,28 It has been postulated that the higher sensitivity of the immature myocardium to afterload compared to infants, children, and adults results in poor contractility in preterm, especially very preterm, neonates. Accordingly, the abrupt increase in left ventricular afterload following the sudden removal of the low-resistance placental vascular bed at the time of cord clamping is thought to be one of the primary causes of myocardial dysfunction in very preterm neonates in the immediate postnatal period.

Another major cause of myocardial dysfunction is hypoxic-ischemic injury associated with perinatal depression.^{29, 30, and 31} In this setting, the compensatory vasoconstriction may mask the impending circulatory failure by maintaining BP in the perceived normal range. Therefore, assessment of myocardial function by echocardiography has been recommended in all patients with low Apgar scores or evidence of perinatal depression.³²

Disturbances of Afterload

Afterload and SVR are often used interchangeably. However, although related, they do not represent the same hemodynamic entity. SVR is a calculated value based on the pressure gradient (the pressure difference between systemic mean arterial BP and central venous pressure) and CO. Conversely, afterload is the pressure or force that the myocardium has to overcome during the isovolumetric contraction time to eject blood out of the left ventricle into the aorta during the ejection time. The Laplace law describes afterload as the ventricular muscle tension being directly related to the pressure and the diameter of the left ventricle and inversely related to muscle thickness. Because the intraventricular pressure needed to open the aortic valve depends on the BP in the aorta and because SVR, through its interaction with CO, determines the BP, SVR is directly related to afterload. However, changes in left ventricular diameter or myocardial wall thickness will also alter the afterload without changes in the SVR. In summary, afterload and SVR are not the same and should not be used interchangeably.

As mentioned, high afterload has been implicated in the pathogenesis of circulatory failure in very preterm infants in the immediate postnatal period. Increased afterload also contributes to worsening hypotension and impaired tissue perfusion in settings of a dilated ventricle, such as dilated cardiomyopathy or failing left ventricle, more frequently seen in neonates with asphyxia. Thus, only judicious use of volume expanders is recommended in these settings as the volume administration-associated increases in ventricular size lead to further increases in afterload and worsen the existing myocardial dysfunction.

In certain clinical situations, in addition to low SVR, low afterload can contribute to the development of circulatory failure. For example, in cases with hypertrophic cardiomyopathy, the low afterload caused by the small ventricular cavity and thick myocardium can lead to hyperdynamic myocardial function and therefore worsen the dynamic left ventricular tract obstruction associated with the hypertrophic cardiomyopathy.

Others

Circulatory compromise can also develop when an arterial shunt is present between the systemic and pulmonary circulations, such as seen with a hemodynamically significant patent ductus arteriosus (PDA) or an aortopulmonary collateral. Similarly, arteriovenous connections seen in patients with a large arteriovenous malformation can lead to circulatory compromise. PDA is discussed in another chapter of this book. Suffice it to say that, because of systolic or diastolic “steal” or myocardial dysfunction secondary to left ventricular volume overload with or without reduced coronary blood flow, a persistent hemodynamically significant PDA can result in the development of systemic hypotension and hypoperfusion.^33,34 Although aortopulmonary collaterals are not uncommon in preterm infants with chronic lung disease, they usually are not large enough to cause circulatory failure. Finally, in patients with a large arteriovenous malformation, the left ventricular volume overload can result in heart failure and circulatory compromise.

DIFFERENTIAL DIAGNOSIS

“True” systemic hypotension should be differentiated from factitious ones. Accordingly, when making the diagnosis of hypotension, potential problems with the measurement of BP itself and the uncertainty about the definition of true hypotension both need to be considered.

Blood pressure can be measured noninvasively (most commonly by using the oscillometric technique) or invasively via an umbilical or peripheral artery catheter connected to a pressure transducer. If using the noninvasive oscillometric technique, one must use the correct BP cuff with a ratio of cuff width to arm circumference between 0.45 and 0.7.^13,35 If the cuff size is too small or too large for the given patient, erroneously high or low BP readings, respectively, will be obtained.^13,35 However, with an appropriate-size cuff, accurate estimations of BP are generally obtained, with most studies finding good agreement between oscillometric and invasive techniques.³⁶ On the other hand, in very preterm infants (the population with the highest risk for the development of hypotension), the noninvasive technique might overestimate the BP.³⁷ When invasive BP monitoring via arterial catheters is used, improper setup of the BP monitoring system can result in significant errors. The presence of air bubbles or blood clots in the system can result in dampened waveforms and yield an erroneously low systolic and high diastolic BP, usually resulting in an underestimated mean BP.^36,38 In addition, if the pressure transducer is placed above or below the level of a patient’s heart, an erroneously low or high BP, respectively, is recorded. However, these technical issues can be readily addressed once identified.

On the other hand, the problem of appropriately defining true hypotension, which will then merit treatment, is much more difficult to solve (see the section on the definition of hypotension). At present, the available bedside monitoring tools and clinical and laboratory indicators used in the assessment of the status of the cardiovascular system are unreliable and not evidence based. However, by using the appropriately obtained BP value in combination with the concurrently monitored additional cardiovascular parameters, such as heart rate, arterial oxygen saturation, and perhaps regional tissue oxygen saturation obtained via near-infrared spectroscopy, as well as by taking the findings of the physical examination and laboratory studies (capillary refill time [CRT], urine output, and serum lactate levels) into consideration, one may be able to more appropriately assess the status of the cardiovascular system and make a reasonable decision about the need for treatment. Once it has been decided that the given BP represents true hypotension, the next step is to identify the underlying etiology (Table 20-1) because the treatment must be tailored to the etiology and pathophysiology of the cardiovascular compromise. Finally, it must be emphasized again that, although we have evidence on short-term hemodynamic effects of the medications most frequently used in the treatment of neonatal hypotension, such as dopamine, dobutamine, epinephrine, and perhaps milrinone, we do not have evidence-based mortality and long-term outcome data and thus clinically relevant evidence on the safety and appropriateness of the presently used treatment of neonatal hypotension.^{3, 4, and 5,19}

DIAGNOSTIC TESTS

In the assessment of the adequacy of tissue perfusion in neonates with the clinical diagnosis of hypotension, a number of clinical and laboratory tests have been used. Although these tests, especially when used in combination, enhance our ability to detect circulatory compromise, they also carry significant limitations. Newer bedside tools such as near-infrared and visible light spectroscopy, laser tissue Doppler, amplitude-integrated electroencephalography, electrical impedance cardiometry, and functional echocardiography provide more objective data on the status of the cardiovascular system and are promising.²⁰

Among the clinical tests, CRT is commonly used and can provide information on the peripheral circulation. CRT is assessed by pressing the skin for 3 to 5 seconds to cause blanching by emptying the capillary bed; then, the time it takes for the capillary bed to refill and return to the baseline color is measured. Forehead and sternum are most likely the best places to measure CRT.^39,40 A CRT greater than 3 seconds is considered abnormal.^39,40 However, the predictive value of CRT for systemic hypoperfusion is poor. Although some improvements can be achieved by combining prolonged CRT with hypotension or other markers of hypoperfusion (eg, serum lactate levels), the sensitivity remains too low for CRT to be clinically useful.^{39, 40, 41, and 42}

Another parameter that usually changes during circulatory compromise is the heart rate, and an elevated heart rate compared to the baseline may indicate low CO. However, as tachycardia can occur with many conditions (eg, fever, sepsis, pain, agitation, and as a side effect of certain medications), its value in the diagnosis of shock is limited. On the other hand, changes in heart rate pattern can be used to predict impending sepsis and thus, potentially, septic shock.⁴³

Urine output can be used as an indirect method of assessment of adequacy of renal blood flow. Because, from a hemodynamic standpoint, the kidneys are considered nonvital organs, renal perfusion is among the first to change. Therefore, a decrease in urine output could be a sign of impending cardiovascular failure. In general, a urine output greater than 1–2 mL/kg/min suggests adequate renal perfusion during the first postnatal days. However, monitoring urine output to determine the adequacy of BP in a timely manner can be problematic as detection of low urine output usually takes hours after renal perfusion has decreased. In addition, low urine output may also be the result of causes unrelated to BP.

Serum lactate level is another indirect marker of tissue perfusion. In the absence of an inborn error of metabolism, elevated serum lactate levels suggest anaerobic metabolism as a consequence of poor tissue perfusion. However, similar to low urine output, high serum lactate only tells us about the lack of adequate tissue perfusion hours earlier and therefore may not be useful in determining the adequacy of BP and tissue perfusion in real time. Furthermore, as serum lactate is increased with epinephrine infusion independently of the status of tissue perfusion, a high serum lactate level may not be reflective of a perfusion problem in the epinephrine-exposed neonate.⁴⁴ However, repeated follow-up of serum lactate over time can be useful for the assessment of longer-term hemodynamic response to treatment.

Assessment of tissue perfusion using near-infrared and visible light spectroscopy might also be useful in the overall assessment of circulatory function.^{46, 47, 48, and 49} However, routine application of these new techniques requires further evaluation. ^46,48,49 Functional echocardiography allows for identifying the underlying pathophysiology of hypotension and should be considered in all patients with hemodynamic instability.^32,50 Assessment of myocardial contractility and the presence of pericardial effusion or a large PDA with a left-to-right shunt is relatively straightforward and important in determining the cause of hypotension. More detailed interrogation of cardiovascular function may include estimation of left and right ventricular output and superior vena cava flow as well as assessment of the load-dependent and load-independent measures of myocardial contractility (shortening fraction and stress-velocity index, respectively), diastolic function, pulmonary artery pressure, the hemodynamic significance of a PDA, and selective organ blood flows.

Although functional echocardiography can be helpful in the diagnosis and management of neonatal hypotension and shock, it has a number of shortcomings as well. Functional echocardiography requires the availability of expensive equipment and expert operators with the skill needed to perform and interpret the studies in the NICU 24/7, and it only provides a noncontinuous assessment of the dynamically changing cardiovascular system.^32,50

Recent findings suggest that noninvasive, continuous, beat-to-beat CO monitoring using thoracic bioimpedance technology (electrical impedance cardiometry) has an accuracy and precision in neonates comparable to those of echocardiography.^51,52 However, further studies are needed to validate the utility of electrical cardiometry in the clinical setting. It must also be noted that, if appropriately validated, electrical impedance cardiometry will be used in conjunction with and not instead of echocardiography.

MANAGEMENT

As stated previously, when discussing the management of neonates presenting with hypotension and systemic hypoperfusion, we must acknowledge the lack of information from randomized placebo-controlled clinical trials on the safety and clinically relevant, long-term benefits of correcting systemic hypotension, especially in the very preterm neonate in the immediate postnatal period. However, designing such a trial is challenging. Uncertainty about the gestational and chronological age-specific definition of hypotension, the type of treatment (volume, vasopressor-inotropes, inotropes, or lusitropes) appropriate for the underlying pathophysiology of the cardiovascular compromise in each patient (individualized treatment strategy); and the ability to adequately monitor in real time the comprehensive hemodynamic response elicited (BP, CO, SVR, and organ blood flow together) rather than only heart rate, oxygen saturation, and BP are among the main challenges of designing such a clinical trial. Furthermore, timely enrollment of the subjects and willingness of the participating clinician to randomize the hypotensive patients to the placebo arm are other issues to be resolved before such a trial may become feasible.⁵³

In summary, the use of comprehensive hemodynamic monitoring allowing for the timely diagnosis and recognition of the underlying pathophysiology of the cardiovascular compromise and for appropriate selection and monitoring of the hemodynamic response of treatment as well as the selection of the most appropriate short-term hemodynamic and long-term, clinically relevant outcome measures are the most important challenges the designers of these trials face. In addition, patient populations with different gestational and postnatal ages will have to be stratified and studied separately. It is no wonder we do not have evidence yet on the safety and clinically relevant long-term effects of treatment of neonatal hypotension in preterm or term neonates.

While awaiting the findings of such well-designed placebo-controlled and appropriately executed studies, attention to the principles of developmental cardiovascular physiology, pathophysiology, and pharmacology⁵⁴ will likely aid in increasing the likelihood of recovery and decreasing the rate of adverse effects of hypotension and its treatment. Accordingly, taking into consideration the following points might help the clinician in the decision making process: (1) using one of the most relevant current definitions of hypotension as one of the available screening tools; (2) using clinical and laboratory indicators of adequacy of perfusion as adjuncts to BP; (3) identifying the underlying pathophysiology using the history, physical examination, and appropriate hemodynamic monitoring, including functional echocardiography; (4) addressing the underlying pathophysiology with an appropriate treatment strategy by choosing the most appropriate medication based on the hemodynamic derangement and the pharmacokinetics and pharmacodynamics of the given drug; (5) appropriately titrating the medication to the desired effect; (6) considering downregulation of adrenergic receptors to adjust the dose or use additional treatment, such as hydrocortisone,⁵⁵ to upregulate the receptors and intracellular enzyme systems involved in eliciting the hemodynamic response in the heart and vasculature; and (7) avoiding, or at least minimizing, significant fluctuations in BP and systemic and organ blood flow in response to treatment.

OUTCOME AND FOLLOW-UP

The impact of hypotension and its treatment on clinically relevant long-term outcome measures is unclear. There are many obstacles in evaluating the true effects of hypotension on neurodevelopmental outcome. The main challenge is the lack of any data from prospective studies or randomized controlled trials on the effects of untreated hypotension on short- and long-term outcome measures. The lack of appropriate data stems from the notion that, via its adverse effect on CBF and oxygen delivery, hypotension leads to brain injury. The association between hypotension and brain injury described in the literature has strengthened this notion.^{6,56, 57, 58, and 59} Therefore, clinicians have been reluctant to enroll hypotensive patients in placebo-controlled randomized clinical trials designed to define hypotension based on the known effects on organ injury of true hypotension. Indeed, a recent clinical study found that a randomized clinical trial of treatment vs placebo in the very preterm population was not feasible.⁵³ While obtaining parental consent was the main obstacle in this trial, the clinicians’ bias also played a major role as 22% of the eligible patients were not considered for enrollment by the treating neonatologists and 85% of the eligible patients who were not enrolled received treatment for hypotension.

Another challenge in elucidating the potential role of hypotension in extremely preterm infants with impaired long-term neurodevelopmental outcome is the presence of confounding factors. As hypotension most commonly occurs during the first few days after birth, other coexisting hemodynamic factors during the transitional period, such as myocardial dysfunction, PDA, upregulated inflammatory mediators, oxygen toxicity, and acid-base imbalance, are frequently present, and these factors by themselves have been associated with poor outcome.¹⁶ In addition, the intended (eg, permissive hypercarbia) and unintended (high mean airway pressure) consequences of the respiratory management also affect CBF independent of the presence or absence of hypotension.^{60, 61, 62, 63, and 64} Finally, the lack of a gestational and postnatal age-dependent definition of hypotension based on physiology, pathophysiology, and clinically relevant outcome measures makes it difficult and, at present, likely not even feasible to appropriately define the patient population that truly has hypotension and thus could benefit from treatment.^16,19

Among the hemodynamic factors that may determine whether a hypotensive preterm infant would have a poor outcome, the duration of hypotension,^56,64,65 response to treatment,⁶⁶ presence of metabolic acidosis,⁵⁷ and problems with perfusion^12,65 have been identified as potentially important factors. Of course, many other factors unrelated to hypotension or hemodynamic instability, including but not restricted to the degree of immaturity, presence of brain injury, infection, oxygen toxicity, maternal socioeconomic status, and other things, play a major role in long-term outcome.

Although some studies suggest otherwise,^67,68 the current literature is fairly consistent in that patients who have BP in the perceived normal range have better outcomes in general than those who become hypotensive.^{7,8,12,55,56,62, 63, 64, 66, and 66,69, 70, and 71} However, it is unclear whether hypotension itself, its treatment, both, neither, or a combination of some or all of these factors are responsible for the poor outcomes. Most of the earlier studies have attributed the associated poor outcome to hypotension, while some of the more recent studies blamed the treatment for the complications. However, the fact is that the relationship between hypotension or its treatment with poor outcomes is one of association, and causality cannot be determined from the available data. Therefore, depending on our bias, we will continue to attribute the poor outcome to hypotension or its treatment until appropriately designed and executed clinical trials finally address this long-lasting controversy.

REFERENCES