Pathophysiology

The pulmonary valve annulus may range from being nearly normal in size to being severely hypoplastic. The valve itself is often bicuspid or unicuspid and, occasionally, is the only site of stenosis. More commonly, the subpulmonic or infundibular muscle, known as the crista supraventricularis, is hypertrophic, which contributes to the subvalvar stenosis and results in an infundibular chamber of variable size and contour. When the right ventricular outflow tract is completely obstructed (pulmonary atresia), the anatomy of the branch pulmonary arteries is extremely variable. A main pulmonary artery segment may be in continuity with right ventricular outflow, separated by a fibrous but imperforate pulmonary valve; the main pulmonary artery may be moderately or severely hypoplastic but still supply part or all of the pulmonary bed; or the entire main pulmonary artery segment may be absent. Occasionally, the branch pulmonary arteries may be discontinuous. Pulmonary blood flow may be supplied by a patent ductus arteriosus (PDA) or by multiple major aortopulmonary collateral arteries (MAPCAs) arising from the ascending and descending aorta and supplying various lung segments.

The VSD is usually nonrestrictive and large, is located just below the aortic valve, and is related to the posterior and right aortic cusps. Rarely, the VSD may be in the inlet portion of the ventricular septum (atrioventricular septal defect). The normal fibrous continuity of the mitral and aortic valves is usually maintained, and if not (due to the presence of a subaortic muscular conus) the classification is usually that of double outlet right ventricle (Chapter 424.5). The aortic arch is right sided in 20% of cases, and the aortic root is usually large and overrides the VSD to varying degrees. When the aorta overrides the VSD by more than 50% and if there is a subaortic conus, this defect is classified as a form of double-outlet right ventricle; however, the circulatory dynamics are the same as that of tetralogy of Fallot.

Systemic venous return to the right atrium and right ventricle is normal. When the right ventricle contracts in the presence of marked pulmonary stenosis, blood is shunted across the VSD into the aorta. Persistent arterial desaturation and cyanosis result, the degree dependent on the severity of the pulmonary obstruction. Pulmonary blood flow, when severely restricted by the obstruction to right ventricular outflow, may be supplemented by a PDA. Peak systolic and diastolic pressures in each ventricle are similar and at systemic level. A large pressure gradient occurs across the obstructed right ventricular outflow tract, and pulmonary arterial pressure is either normal or lower than normal. The degree of right ventricular outflow obstruction determines the timing of the onset of symptoms, the severity of cyanosis, and the degree of right ventricular hypertrophy. When obstruction to right ventricular outflow is mild to moderate and a balanced shunt is present across the VSD, the patient may not be visibly cyanotic (acyanotic or “pink” tetralogy of Fallot). When obstruction is severe, cyanosis will be present from birth and worsen when the ductus begins to close.

Clinical Manifestations

Infants with mild degrees of right ventricular outflow obstruction may initially be seen with heart failure caused by a ventricular-level left-to-right shunt. Often, cyanosis is not present at birth; but with increasing hypertrophy of the right ventricular infundibulum as the patient grows, cyanosis occurs later in the 1st yr of life. In infants with severe degrees of right ventricular outflow obstruction, neonatal cyanosis is noted immediately. In these infants, pulmonary blood flow may be partially or nearly totally dependent on flow through the ductus arteriosus. When the ductus begins to close in the 1st few hours or days of life, severe cyanosis and circulatory collapse may occur. Older children with long-standing cyanosis who have not undergone surgery may have dusky blue skin, gray sclerae with engorged blood vessels, and marked clubbing of the fingers and toes. Extracardiac manifestations of long-standing cyanotic congenital heart disease are described in Chapter 428.

In older children with unrepaired tetralogy, dyspnea occurs on exertion. They may play actively for a short time and then sit or lie down. Older children may be able to walk a block or so before stopping to rest. Characteristically, children assume a squatting position for the relief of dyspnea caused by physical effort; the child is usually able to resume physical activity after a few minutes of squatting. These findings occur most often in patients with significant cyanosis at rest.

Paroxysmal hypercyanotic attacks (hypoxic, “blue,” or “tet” spells) are a particular problem during the 1st 2 yr of life. The infant becomes hyperpneic and restless, cyanosis increases, gasping respirations ensue, and syncope may follow. The spells occur most frequently in the morning on initially awakening or after episodes of vigorous crying. Temporary disappearance or a decrease in intensity of the systolic murmur is usual as flow across the right ventricular outflow tract diminishes. The spells may last from a few minutes to a few hours. Short episodes are followed by generalized weakness and sleep. Severe spells may progress to unconsciousness and, occasionally, to convulsions or hemiparesis. The onset is usually spontaneous and unpredictable. Spells are associated with reduction of an already compromised pulmonary blood flow, which, when prolonged, results in severe systemic hypoxia and metabolic acidosis. Infants who are only mildly cyanotic at rest are often more prone to the development of hypoxic spells because they have not acquired the homeostatic mechanisms to tolerate rapid lowering of arterial oxygen saturation, such as polycythemia.

Depending on the frequency and severity of hypercyanotic attacks, one or more of the following procedures should be instituted in sequence: (1) placement of the infant on the abdomen in the knee-chest position while making certain that the infant’s clothing is not constrictive, (2) administration of oxygen (although increasing inspired oxygen will not reverse cyanosis caused by intracardiac shunting), and (3) injection of morphine subcutaneously in a dose not in excess of 0.2 mg/kg. Calming and holding the infant in a knee-chest position may abort progression of an early spell. Premature attempts to obtain blood samples may cause further agitation and be counterproductive.

Because metabolic acidosis develops when arterial PO₂ is <40 mm Hg, rapid correction (within several minutes) with intravenous administration of sodium bicarbonate is necessary if the spell is unusually severe and the child shows a lack of response to the foregoing therapy. Recovery from the spell is usually rapid once the pH has returned to normal. Repeated blood pH measurements may be necessary because rapid recurrence of acidosis may ensue. For spells that are resistant to this therapy, intubation and sedation are often sufficient to break the spell. Drugs that increase systemic vascular resistance, such as intravenous phenylephrine, can improve right ventricular outflow, decrease the right-to-left shunt, and improve the symptoms. β-Adrenergic blockade by the intravenous administration of propranolol (0.1 mg/kg given slowly to a maximum of 0.2 mg/kg) has also been used. Growth and development may be delayed in patients with severe untreated tetralogy of Fallot, particularly when their oxygen saturation is chronically <70%. Puberty may also be delayed in patients who have not undergone surgery.

The pulse is usually normal, as are venous and arterial pressures. In older infants and children, the left anterior hemithorax may bulge anteriorly because of long-standing right ventricular hypertrophy. A substernal right ventricular impulse can usually be detected. A systolic thrill may be felt along the left sternal border in the 3rd and 4th parasternal spaces. The systolic murmur is usually loud and harsh; it may be transmitted widely, especially to the lungs, but is most intense at the left sternal border. The murmur is generally ejection in quality at the upper sternal border, but it may sound more holosystolic toward the lower sternal border. It may be preceded by a click. The murmur is caused by turbulence through the right ventricular outflow tract. It tends to become louder, longer, and harsher as the severity of pulmonary stenosis increases from mild to moderate; however, it can actually become less prominent with severe obstruction, especially during a hypercyanotic spell due to shunting of blood away from the right ventricular outflow through the aortic valve. Either the 2nd heart sound is single, or the pulmonic component is soft. Infrequently, a continuous murmur may be audible, especially if prominent collaterals are present.

Diagnosis

Roentgenographically, the typical configuration as seen in the anteroposterior view consists of a narrow base, concavity of the left heart border in the area usually occupied by the pulmonary artery, and normal overall heart size. The hypertrophied right ventricle causes the rounded apical shadow to be uptilted so that it is situated higher above the diaphragm than normal and pointing horizontally to the left chest wall. The cardiac silhouette has been likened to that of a boot or wooden shoe (“coeur en sabot”) (Fig. 424-2). The hilar areas and lung fields are relatively clear because of diminished pulmonary blood flow or the small size of the pulmonary arteries, or both. The aorta is usually large, and in about 20% of patients it arches to the right, which results in an indentation of the leftward-positioned air-filled tracheobronchial shadow in the anteroposterior view.

Figure 424-2 Chest x-ray of an 8 yr old boy with the tetralogy of Fallot. Note the normal heart size, some elevation of the cardiac apex, concavity in the region of the main pulmonary artery, right-sided aortic arch, and diminished pulmonary vascularity.

The electrocardiogram demonstrates right axis deviation and evidence of right ventricular hypertrophy. A dominant R wave appears in the right precordial chest leads (Rs, R, qR, qRs) or an RSR′ pattern. In some cases, the only sign of right ventricular hypertrophy may initially be a positive T wave in leads V₃R and V₁. The P wave is tall and peaked suggesting right atrial enlargement (see Fig. 417-6).

Two-dimensional echocardiography establishes the diagnosis (Fig. 424-3) and provides information about the extent of aortic override of the septum, the location and degree of the right ventricular outflow tract obstruction, the size of the pulmonary valve annulus and main and proximal branch pulmonary arteries, and the side of the aortic arch. The echocardiogram is also useful in determining whether a PDA is supplying a portion of the pulmonary blood flow. In a patient without pulmonary atresia, echocardiography usually obviates the need for catheterization before surgical repair.

Figure 424-3 Echocardiogram in a patient with the tetralogy of Fallot. This parasternal long-axis two-dimensional view demonstrates anterior displacement of the outflow ventricular septum that resulted in stenosis of the subpulmonic right ventricular outflow tract, overriding of the aorta, and an associated ventricular septal defect. Ao, overriding aorta; LA, left atrium; LV, left ventricle; RV, right ventricle.

Cardiac catheterization demonstrates a systolic pressure in the right ventricle equal to the systemic pressure, since the right ventricle is connected directly to the overriding aorta. If the pulmonary artery is entered, the pressure is markedly decreased, although crossing the right ventricular outflow tract, especially in severe cases, may precipitate a tet spell. Pulmonary arterial pressure is usually lower than normal, in the range of 5-10 mm Hg. The level of arterial oxygen saturation depends on the magnitude of the right-to-left shunt; in “pink tets,” the systemic oxygen saturation may be normal, whereas in a moderately cyanotic patient at rest, it is usually 75-85%.

Selective right ventriculography will demonstrate all of the anatomical features. Contrast medium outlines the heavily trabeculated right ventricle. The infundibular stenosis varies in length, width, contour, and distensibility (Fig. 424-4). The pulmonary valve is usually thickened, and the annulus may be small. In patients with pulmonary atresia and VSD, echocardiography alone is not adequate to assess the anatomy of the pulmonary arteries and MAPCAs. Cardiac CT is extremely helpful, and cardiac catheterization with injection into each arterial collateral is indicated. Complete and accurate information regarding the size and peripheral distribution of the main pulmonary arteries and any collateral vessels (MAPCAs) is important when evaluating these children as surgical candidates.

Figure 424-4 Lateral view of a selective right ventriculogram in a patient with the tetralogy of Fallot. The arrow points to an infundibular stenosis that is below the infundibular chamber (C). The narrowed pulmonary valve orifice is seen at the distal end of the infundibular chamber.

Aortography or coronary arteriography outlines the course of the coronary arteries. In 5-10% of patients with the tetralogy of Fallot, coronary artery abnormalities may be present, most commonly an aberrant coronary artery crossing over the right ventricular outflow tract; this artery must not be cut during surgical repair. Verification of normal coronary arteries is important when considering surgery in young infants who may need a patch across the pulmonary valve annulus. Echocardiography can usually delineate the coronary artery anatomy; angiography is reserved for cases in which questions remain.

Complications

Before the age of corrective surgery, patients with tetralogy of Fallot were susceptible to several serious complications. For this reason, most children undergo complete repair (or in some cases palliation) in infancy, and therefore these days these complications are rare. Cerebral thromboses, usually occurring in the cerebral veins or dural sinuses and occasionally in the cerebral arteries, are a sequelae of extreme polycythemia and dehydration. Thromboses occur most often in patients younger than 2 yr. These patients may have iron-deficiency anemia, frequently with hemoglobin and hematocrit levels in the normal range (but too low for cyanotic heart disease). Therapy consists of adequate hydration and supportive measures. Phlebotomy and volume replacement with albumin or saline are indicated in extremely polycythemic patients who are symptomatic.

Brain abscess is less common than cerebral vascular events and extremely rare today. Patients with a brain abscess are usually older than 2 yr. The onset of the illness is often insidious and consists of low-grade fever or a gradual change in behavior, or both. Some patients have an acute onset of symptoms that may develop after a recent history of headache, nausea, and vomiting. Seizures may occur; localized neurologic signs depend on the site and size of the abscess and the presence of increased intracranial pressure. CT or MRI confirms the diagnosis. Antibiotic therapy may help keep the infection localized, but surgical drainage of the abscess is usually necessary (Chapter 596).

Bacterial endocarditis may occur in the right ventricular infundibulum or on the pulmonic, aortic, or, rarely, tricuspid valves. Endocarditis may complicate palliative shunts or, in patients with corrective surgery, any residual pulmonic stenosis or VSD. Heart failure is not a usual feature in patients with tetralogy of Fallot, with the exception of some young infants with “pink” or acyanotic tetralogy of Fallot. As the degree of pulmonary obstruction worsens with age, the symptoms of heart failure resolve and eventually the patient experiences cyanosis, often by 6-12 mo of age. These patients are at increased risk for hypercyanotic spells at this time.

Associated Anomalies

A PDA may be present, and defects in the atrial septum are occasionally seen. A right aortic arch occurs in ≈20% of patients, and other anomalies of the pulmonary arteries and aortic arch may also be seen. Persistence of a left superior vena cava draining into the coronary sinus is common but not a concern. Multiple VSDs are occasionally present and must be diagnosed before corrective surgery. Coronary artery anomalies are present in 5-10% and can complicate surgical repair. Tetralogy of Fallot may also occur with an atrioventricular septal defect, often associated with Down syndrome.

Congenital absence of the pulmonary valve produces a distinct syndrome that is usually marked by signs of upper airway obstruction (Chapter 422.1). Cyanosis may be absent, mild, or moderate; the heart is large and hyperdynamic; and a loud to-and-fro murmur is present. Marked aneurysmal dilatation of the main and branch pulmonary arteries results in compression of the bronchi and produces stridulous or wheezing respirations and recurrent pneumonia. If the airway obstruction is severe, reconstruction of the trachea at the time of corrective cardiac surgery may be required to alleviate the symptoms.

Absence of a branch pulmonary artery, most often the left, should be suspected if the roentgenographic appearance of the pulmonary vasculature differs on the two sides; absence of a pulmonary artery is often associated with hypoplasia of the affected lung. It is important to recognize the absence of a pulmonary artery because occlusion of the remaining pulmonary artery during surgery seriously compromises the already reduced pulmonary blood flow.

As one of the conotruncal malformations, tetralogy of Fallot can be associated with DiGeorge syndrome or Shprintzen velocardiofacial syndrome, also known by the acronym CATCH 22 (cardiac defects, abnormal facies, thymic hypoplasia, cleft palate, hypocalcemia). Cytogenetic analysis using fluorescence in situ hybridization demonstrates deletions of a large segment of chromosome 22q11 known as the DiGeorge critical region. Deletion or mutation of the gene encoding the transcription factor Tbx1 has been implicated as a possible cause of DiGeorge syndrome, although several other genes have been identified as possible candidates or modifier genes.

Treatment

Treatment of tetralogy of Fallot depends on the severity of the right ventricular outflow tract obstruction. Infants with severe tetralogy require urgent medical treatment and surgical intervention in the neonatal period. Therapy is aimed at providing an immediate increase in pulmonary blood flow to prevent the sequelae of severe hypoxia. The infant should be transported to a medical center adequately equipped to evaluate and treat neonates with congenital heart disease under optimal conditions. Prolonged, severe hypoxia may lead to shock, respiratory failure, and intractable acidosis and will significantly reduce the chance of survival, even when surgically amenable lesions are present. It is critical that normal body temperature be maintained during the transfer since cold increases oxygen consumption, which places additional stress on a cyanotic infant, whose oxygen delivery is already limited. Blood glucose levels should be monitored because hypoglycemia is more likely to develop in infants with cyanotic heart disease.

Neonates with marked right ventricular outflow tract obstruction may deteriorate rapidly because, as the ductus arteriosus begins to close, pulmonary blood flow is further compromised. The intravenous administration of prostaglandin E₁ (0.01-0.20 µg/kg/min), a potent and specific relaxant of ductal smooth muscle, causes dilatation of the ductus arteriosus and usually provides adequate pulmonary blood flow until a surgical procedure can be performed. This agent should be administered intravenously as soon as cyanotic congenital heart disease is clinically suspected and continued through the preoperative period and during cardiac catheterization. Because prostaglandin can cause apnea, an individual skilled in neonatal intubation should be readily available.

Infants with less severe right ventricular outflow tract obstruction who are stable and awaiting surgical intervention require careful observation. Acyanotic patients can fairly quickly progress to having cyanotic episodes. Prevention or prompt treatment of dehydration is important to avoid hemoconcentration and possible thrombotic episodes. Oral propranolol (0.5-1 mg/kg every 6 hr) had been used in the past to decrease the frequency and severity of hypercyanotic spells, but with the excellent surgical results available today, surgical treatment is now indicated as soon as spells begin.

Infants with symptoms and severe cyanosis in the 1st mo of life usually have marked obstruction of the right ventricular outflow tract. Two options are available in these infants. The first is corrective open heart surgery performed in early infancy and even in the newborn period in critically ill infants. This approach has widespread acceptance today with excellent short- and long-term results and has supplanted palliative shunts (see later) for most cases. Early total repair carries the theoretical advantage that early physiologic correction allows for improved growth of the branch pulmonary arteries. In infants with less severe cyanosis who can be maintained with good growth and absence of hypercyanotic spells, primary repair is performed electively at between 4 and 6 mo of age.

Corrective surgical therapy consists of relief of the right ventricular outflow tract obstruction by resecting obstructive muscle bundles and by patch closure of the VSD. If the pulmonary valve is stenotic, as it usually is, a valvotomy is performed. If the pulmonary valve annulus is too small or the valve is extremely thickened, a valvectomy may be performed, the pulmonary valve annulus split open, and a transannular patch placed across the pulmonary valve ring. The surgical risk of total correction in major centers is <5%. A right ventriculotomy was once the standard approach; a transatrial-transpulmonary approach is routinely performed to reduce the long-term risks of a large right ventriculotomy. In patients in whom repair has been delayed to childhood, increased bleeding in the immediate postoperative period may be a complicating factor due to their extreme polycythemia.

The second option, more common in previous years, is a palliative systemic-to-pulmonary artery shunt (Blalock-Taussig shunt) performed to augment pulmonary artery blood flow. The rationale for this surgery, previously the only option for these patients, is to augment pulmonary blood flow to decrease the amount of hypoxia and improve linear growth, as well as augment growth of the branch pulmonary arteries. The modified Blalock-Taussig shunt is currently the most common aortopulmonary shunt procedure and consists of a Gore-Tex conduit anastomosed side to side from the subclavian artery to the homolateral branch of the pulmonary artery (Fig. 424-5). Sometimes the shunt is brought directly from the ascending aorta to the main pulmonary artery and in this case is called a central shunt. The Blalock-Taussig operation can be successfully performed in the newborn period with shunts 3-4 mm in diameter and has also been used successfully in premature infants.

Figure 424-5 Physiology of a Blalock-Taussig shunt in a patient with the tetralogy of Fallot. Circled numbers represent oxygen saturation values. The intracardiac shunting pattern is as described for Figure 424-1

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