**6.1 Tetralogy of Fallot**

Tetralogy of Fallot (TOF) is the most common cause of cyanosis beyond one year of age and constitutes 10% of all congenital heart defects. Fallot defined it as a constellation of four abnormalities to include a VSD, PS, right ventricular hypertrophy and dextroposition of the aorta. The ventricular defect is always large and non-restrictive and is located in the membranous septum in the subaortic region. Pulmonary stenosis is variable in severity and nature of obstruction. The right ventricular outflow obstruction may be mild resulting in initial left-to-right shunt at ventricular level or it may be severe causing severe cyanosis

Congenital Heart Defects – A Review 29

mechanism. Prevention of these spells by beta-adrenergic blockade may further support this hypothesis. Since the spells have also been observed in patients with VSD and pulmonary atresia in whom infundibular spasm is singularly irrelevant, it is unlikely that the infundibular spasm is the cause in all cases. Another mechanism proposed is paroxysmal hyperpnea. During sleep oxygen consumption is reduced and there is a normal acid base balance. When the infant awakens the O2 consumption increases and there is a slight acid base imbalance. There are adjustments made by the respiratory center to bring the imbalance back to normal. But, if there is a sudden increase in activity and consequent increase in oxygen consumption before the adjustments occur, decrease in PO2 and pH and increase in PCO2 take place triggering a hyperpnea response from the respiratory center and enter a vicious cycle. Hyperpnea reduces mean intrathoracic pressure, which decreases systemic and pulmonary resistances. Decreased systemic resistance is not matched with increased pulmonary flow because of dominant right ventricular outflow tract obstruction. Thus, there is even greater right-to-left shunt, further decreasing the PO2 and pH and thus a vicious cycle (Guntheroth et al 1965, Rao 1983). Most workers believe that this is the most

Central cyanosis is observed in most cases of' tetralogy of Fallot. However, it should be noted that mild arterial desaturation may not cause clinically detectable cyanosis. Clubbing of fingers and toes is observed beyond the first few months of life. There are usually no signs of congestive heart failure. Prominent right ventricular impulse or heave may be present. A systolic thrill may be present at the left upper sternal border. The first heart sound may be normal or slightly increased. The second heart sound is single without an audible pulmonary component. A grade III-IV/Vl long ejection systolic murmur, caused by blood flow through the right ventricular outflow tract, is usually heard at the left upper sternal border. In contrast to PS with intact ventricular septum, the murmur of tetralogy becomes shorter and less intense with increasing severity of PS. During hypercyanotic spell the murmur disappears or becomes very soft. A holosystolic murmur of VSD may be heard at the left lower sternal border in some children especially in less severe and acyanotic forms of tetralogy of Fallot. Early diastolic murmurs do not occur with TOF; the exception is TOF with syndrome of absent pulmonary valve. Continuous murmur of associated PDA is rarely heard. Older children may have an audible continuous murmur of bronchial collateral flow

On a chest roentgenogram the heart size is usually normal to minimally increased. An uplifted apex, thought to indicate right ventricular hypertrophy may be present and is described by some as "boot-shaped" heart. Concavity in the region of pulmonary conus, reflecting hypoplasia of the pulmonary outflow tract may be present. Pulmonary vascular markings are usually diminished. A right sided aortic arch may be present. While a right aortic arch is expected to be present in 25% of TOF patients, the presence of a right aortic arch along with concave pulmonary conus and decreased pulmonary vascular markings in a

likely mechanism for the development of spells.

**6.1.2 Physical examination** 

into the lungs.

**6.1.3 Noninvasive evaluation 6.1.3.1 Chest roentgenogram** 

chest x-ray makes the diagnosis of TOF virtually certain.

even in the neonatal period. It may be completely obstructed (pulmonary atresia) so that there is no forward flow from the right ventricle into the pulmonary artery, thus ductal dependent. The obstruction may be infundibular, valvar or supravalvar in nature or may involve branch pulmonary arteries. The stenotic component may be at a single site or may involve multiple sites. Infundibular obstruction is the most common obstruction in TOF and is due to malposition of the crista supraventricularis. The valvar stenosis may be due to valve leaflet fusion or due to valve ring hypoplasia. Right ventricular hypertrophy of severe degree is present in all cases. Dextroposition or over-riding of aorta over the ventricular septum is a variable phenomenon. The aorta is large and is thought to be due to a developmental anomaly rather than the result of physiologic abnormality of TOF. Right aortic arch is present in 25% of TOF cases.

Atrial septal defects may be present in 15% of patients with TOF in which case it may be called pentology of Fallot. Coronary artery anomalies are present in a small but significant number of cases. Origin of the left anterior descending coronary artery from the right coronary artery is the most common coronary anomaly in TOF and sometime the course of the coronary artery may be intra-myocardial.

Because the VSD is large, the systolic pressures in both ventricles are equal and for practical purposes both ventricles act as one functional chamber. The quantity of blood flow into to the systemic and pulmonary circuits depends upon their respective resistances. The level of systemic vascular resistance and the resistance offered by the right ventricular outflow tract stenosis determine the flows. The more severe the PS, the less is the pulmonary flow. In the average case of tetralogy of Fallot, the resistance offered by PS is more than that of the systemic vascular tone with consequent right-to-left shunt across the VSD. The consequent cyanosis and hypoxemia stimulate bone marrow (via kidney and erythropoitin) and produce polycythemia. While the polycythemia is helpful in increasing oxygen carrying capacity, it becomes counter-productive when the hematocrit is excessive (60 to 70%).

#### **6.1.1 Symptoms**

The clinical presentation depends upon the degree of PS. With milder degrees of PS, symptoms may not be present until late childhood while with severe PS the presentation may be in the early infancy. Typically the infant may be pink (not cyanotic) as a neonate and develops cyanosis between 2 to 6 months of age. Most usual modes of presentation are asymptomatic murmur discovered on routine auscultation, bluish color (cyanosis) observed by the parent or primary physician, hypercyanotic spells, and decreased exercise tolerance.

Hypercyanotic spells are variously described as anoxic spells, hypoxic spells, blue spells, paroxysmal dyspnea, paroxysmal hyperpnea and so no. The spells characteristically occur in tetralogy although they can be present in other lesions with similar physiology. They can occur any time between 1 month and 12 years of age but the peak incidence is 2 to 3 months. They can occur at any time of the day but most commonly seen after awakening from sleep; crying, defecation and feeding are the common precipitating factors. Spells are characterized by increasing rate and depth of respiration (hyperpnea) with increasing cyanosis, progressing to limpness and syncope, occasionally terminating in convolutions, cerebrovascular accident or death. Spells may occur in tetralogy with mild arterial desaturation and conversely may not be present in patients with severe cyanosis.

The cause or mechanism of onset of spells is not clear. Right ventricular infundibular spasm, precipitated by acute increase in endogenous catacholamines has been proposed as a

even in the neonatal period. It may be completely obstructed (pulmonary atresia) so that there is no forward flow from the right ventricle into the pulmonary artery, thus ductal dependent. The obstruction may be infundibular, valvar or supravalvar in nature or may involve branch pulmonary arteries. The stenotic component may be at a single site or may involve multiple sites. Infundibular obstruction is the most common obstruction in TOF and is due to malposition of the crista supraventricularis. The valvar stenosis may be due to valve leaflet fusion or due to valve ring hypoplasia. Right ventricular hypertrophy of severe degree is present in all cases. Dextroposition or over-riding of aorta over the ventricular septum is a variable phenomenon. The aorta is large and is thought to be due to a developmental anomaly rather than the result of physiologic abnormality of TOF. Right

Atrial septal defects may be present in 15% of patients with TOF in which case it may be called pentology of Fallot. Coronary artery anomalies are present in a small but significant number of cases. Origin of the left anterior descending coronary artery from the right coronary artery is the most common coronary anomaly in TOF and sometime the course of

Because the VSD is large, the systolic pressures in both ventricles are equal and for practical purposes both ventricles act as one functional chamber. The quantity of blood flow into to the systemic and pulmonary circuits depends upon their respective resistances. The level of systemic vascular resistance and the resistance offered by the right ventricular outflow tract stenosis determine the flows. The more severe the PS, the less is the pulmonary flow. In the average case of tetralogy of Fallot, the resistance offered by PS is more than that of the systemic vascular tone with consequent right-to-left shunt across the VSD. The consequent cyanosis and hypoxemia stimulate bone marrow (via kidney and erythropoitin) and produce polycythemia. While the polycythemia is helpful in increasing oxygen carrying capacity, it becomes counter-productive when the hematocrit is excessive (60 to 70%).

The clinical presentation depends upon the degree of PS. With milder degrees of PS, symptoms may not be present until late childhood while with severe PS the presentation may be in the early infancy. Typically the infant may be pink (not cyanotic) as a neonate and develops cyanosis between 2 to 6 months of age. Most usual modes of presentation are asymptomatic murmur discovered on routine auscultation, bluish color (cyanosis) observed by the parent or primary physician, hypercyanotic spells, and decreased exercise tolerance. Hypercyanotic spells are variously described as anoxic spells, hypoxic spells, blue spells, paroxysmal dyspnea, paroxysmal hyperpnea and so no. The spells characteristically occur in tetralogy although they can be present in other lesions with similar physiology. They can occur any time between 1 month and 12 years of age but the peak incidence is 2 to 3 months. They can occur at any time of the day but most commonly seen after awakening from sleep; crying, defecation and feeding are the common precipitating factors. Spells are characterized by increasing rate and depth of respiration (hyperpnea) with increasing cyanosis, progressing to limpness and syncope, occasionally terminating in convolutions, cerebrovascular accident or death. Spells may occur in tetralogy with mild arterial

desaturation and conversely may not be present in patients with severe cyanosis.

The cause or mechanism of onset of spells is not clear. Right ventricular infundibular spasm, precipitated by acute increase in endogenous catacholamines has been proposed as a

aortic arch is present in 25% of TOF cases.

the coronary artery may be intra-myocardial.

**6.1.1 Symptoms** 

mechanism. Prevention of these spells by beta-adrenergic blockade may further support this hypothesis. Since the spells have also been observed in patients with VSD and pulmonary atresia in whom infundibular spasm is singularly irrelevant, it is unlikely that the infundibular spasm is the cause in all cases. Another mechanism proposed is paroxysmal hyperpnea. During sleep oxygen consumption is reduced and there is a normal acid base balance. When the infant awakens the O2 consumption increases and there is a slight acid base imbalance. There are adjustments made by the respiratory center to bring the imbalance back to normal. But, if there is a sudden increase in activity and consequent increase in oxygen consumption before the adjustments occur, decrease in PO2 and pH and increase in PCO2 take place triggering a hyperpnea response from the respiratory center and enter a vicious cycle. Hyperpnea reduces mean intrathoracic pressure, which decreases systemic and pulmonary resistances. Decreased systemic resistance is not matched with increased pulmonary flow because of dominant right ventricular outflow tract obstruction. Thus, there is even greater right-to-left shunt, further decreasing the PO2 and pH and thus a vicious cycle (Guntheroth et al 1965, Rao 1983). Most workers believe that this is the most likely mechanism for the development of spells.

#### **6.1.2 Physical examination**

Central cyanosis is observed in most cases of' tetralogy of Fallot. However, it should be noted that mild arterial desaturation may not cause clinically detectable cyanosis. Clubbing of fingers and toes is observed beyond the first few months of life. There are usually no signs of congestive heart failure. Prominent right ventricular impulse or heave may be present. A systolic thrill may be present at the left upper sternal border. The first heart sound may be normal or slightly increased. The second heart sound is single without an audible pulmonary component. A grade III-IV/Vl long ejection systolic murmur, caused by blood flow through the right ventricular outflow tract, is usually heard at the left upper sternal border. In contrast to PS with intact ventricular septum, the murmur of tetralogy becomes shorter and less intense with increasing severity of PS. During hypercyanotic spell the murmur disappears or becomes very soft. A holosystolic murmur of VSD may be heard at the left lower sternal border in some children especially in less severe and acyanotic forms of tetralogy of Fallot. Early diastolic murmurs do not occur with TOF; the exception is TOF with syndrome of absent pulmonary valve. Continuous murmur of associated PDA is rarely heard. Older children may have an audible continuous murmur of bronchial collateral flow into the lungs.

#### **6.1.3 Noninvasive evaluation**

#### **6.1.3.1 Chest roentgenogram**

On a chest roentgenogram the heart size is usually normal to minimally increased. An uplifted apex, thought to indicate right ventricular hypertrophy may be present and is described by some as "boot-shaped" heart. Concavity in the region of pulmonary conus, reflecting hypoplasia of the pulmonary outflow tract may be present. Pulmonary vascular markings are usually diminished. A right sided aortic arch may be present. While a right aortic arch is expected to be present in 25% of TOF patients, the presence of a right aortic arch along with concave pulmonary conus and decreased pulmonary vascular markings in a chest x-ray makes the diagnosis of TOF virtually certain.

Congenital Heart Defects – A Review 31

right coronary artery occurs in a significant number of cases of TOF and should be excluded,

The goal of management of TOF patients is to allow total surgical correction with minimal mortality and morbidity and to prevent or treat complications inherent to cyanotic heart defects in general and TOF in particular. Protection against subacute bacterial endocarditis, prevention and/or prompt treatment of dehydration, and periodic monitoring for relative anemia secondary to iron deficiency and prompt treatment when found should be undertaken. Palliative or corrective surgical procedures should be performed prior to development of significant polycythemia. Exercise, as tolerated should be permitted unless

Treatment of an infant with cyanotic spell may be summarized (Rao 1989a) as follows: 1. The infant should be placed in a knee-chest position. The reason for its effectiveness appears to be related to its effect in increasing the systemic vascular resistance and thus

2. Humidified oxygen via a facemask should be administered. Since the major defect in the spell syndrome is pulmonary oligemia rather than alveolar hypoxia, oxygen administration has limited usefulness. If the infant is unduly disturbed by the facemask,

3. Morphine sulfate, 0.1 mg/kg subcutaneously, may be effective in aborting the spell. The mechanism of action is not clearly delineated, but its depressive effect on the central nervous system respiratory drive (thus reducing hyperpnea) and sedation of the infant

4. Once the physical examination is completed (and the limited but important laboratory studies are obtained) the infant should be left undisturbed and allowed to rest; this in

5. Correction of metabolic acidosis (with sodium bicarbonate), anemia (by blood transfusion), and dehydration (by appropriate fluids), if present, is very important at

6. If the spell continues, vasopressors to increase the systemic vascular resistance and thus increase the pulmonary blood flow may be tried. In our experience, methoxamine (Vasoxyl) an alpha agonist has been most helpful. It is a pure peripheral vascular stimulator without any direct action on the heart. Methoxamine 20-40 mg in 250 ml of 5% dextrose in water may be administered intravenously; the rate of infusion should be adjusted to increase the systolic blood pressure by 15 to 20% of the control value.

Instead, phenylephrine may be given to increase systemic vascular resistance. 7. Alternatively, propranolol, 0.1 mg/kg body weight, diluted in 50 ml of 5% dextrose in water, may be slowly administered intravenously while monitoring the heart rate (by ECG if possible). Should there be marked bradycardia, propranolol should be stopped. Once it is found to be effective, the infant may be switched to oral propranolol 1-4 mg/kg/day in three and four divided doses. The mechanism of action of propranolol is not clearly understood, but may include negative inotropic effect on the right ventricular infundibular myocardium, prevention of decrease in systemic vascular resistance and/or prevention of ventilatory response (hyperpnea) to hypoxia, all through beta adrenergic blockade. Esmolol, a rapid acting beta blocker, may also be

decreasing the right-to-left shunt and improving the pulmonary flow.

if necessary, by selective coronary angiography.

oxygen therapy may be discontinued.

itself may improve the infant's condition.

symptoms develop with activity.

may be important.

this stage.

**Management** 

### **6.1.3.2 Electrocardiogram**

The ECG shows signs of right ventricular hypertrophy. Right atrial enlargement is less commonly seen.

#### **6.1.3.3 Blood work**

Hemoglobin and hematocrit along with red blood cell indices should be monitored periodically in all children with cyanotic congenital heart defects including TOF. The degree and duration of hypoxemia determine the level of hemoglobin. In the absence of adequate iron intake, relative anemia with hypochromia and microcytosis may develop. Because this is a risk factor for developing cerebrovascular accidents, the relative anemia should be treated with oral supplemental iron.

#### **6.1.3.4 Echocardiogram**

The echo is very helpful in confirming the diagnosis and in evaluating several of the issues related to TOF. Enlargement of the right ventricle, large VSD, aortic over-ride and right ventricular outflow tract obstruction can be imaged. Shunting across the VSD and increased Doppler flow velocity across the right ventricular outflow tract can be demonstrated. Size of the main and proximal branch pulmonary arteries can be evaluated although the distal pulmonary arteries cannot easily be seen by echocardiogram.
