Tetralogy of Fallot

History

• Age of presentation varies by severity of right ventricular pulmonary outflow obstruction
  • Most commonly presents in infancy or neonatal period ^c1
  • Severe right ventricular outflow obstruction presents in neonates ^c2
  • Moderate obstruction
• Prenatal detection
  • Possible; however, right ventricular outflow to lungs in fetus is limited in utero, limiting visualization of typical physiology
  • Usually occurs during evaluation for other congenital anomalies
• Neonates
  • Severe pulmonary outflow obstruction
    • Presents with cyanosis around the time of ductus arteriosus closure (usually first few hours to days of life) ^r5c3
    • Progresses to circulatory collapse without urgent intervention ^r5
• Infants and young children
  • Moderate right ventricular outflow obstruction
    • May present based on abnormal cardiac examination finding (eg, murmur) detected by primary care physician
    • May present with paroxysmal hypercyanotic attacks (ie, blue or tet spells) ^c4c5
      • Characterized by paroxysms of hyperpnea, irritability, and increased cyanosis; syncope may follow
      • Often triggered by agitation or occurs after first morning wakening ^r5
      • Problematic during the first 2 years of life ^r5
      • May last for a few minutes to hours ^r5
      • Episodes are often followed by a short period of generalized weakness and sleep
  • Mild right ventricular outflow obstruction
    • May present with subtle, progressive cyanosis
      • May present later in the first year of life as infundibular hypertrophy increases, resulting in subsequent decrease in pulmonary flow ^r5
    • May present with progressive heart failure
      • Children may play for a period of time and then stop to sit, squat, or lie down to relieve exertional dyspnea ^r5c6
• Older children and adults
  • Uncorrected tetralogy of Fallot is associated with very mild degrees of right ventricular outflow obstruction
    • Rarely presents in older age groups with right-sided heart failure symptoms (eg, dyspnea, exertional syncope, lightheadedness) ^c7c8c9
    • Characteristically, patients assume squatting position to relieve dyspnea caused by physical effort ^r5
  • Chronic pulmonary regurgitation commonly develops in adults following successful repair in early childhood ^r6
    • May present with progressive exercise intolerance, right- or left-sided heart failure symptoms, or tachyarrhythmias

Physical examination

• Cyanosis in the neonatal or infant period is the most common finding ^c10c11
• Cardiac findings
  • Combination of a loud systolic murmur with a single second heart sound is highly characteristic ^c12c13
  • S₂ is single, or pulmonic component of S₂ is soft
  • Murmur is primarily caused by turbulence through right ventricular outflow tract ^r5
    • Usually, loud and harsh
      • Louder, longer, and harsher murmurs suggest increasing severity, from mild to moderate, of right ventricular outflow obstruction; however, severe obstruction often results in a less prominent murmur ^r5
    • Usually systolic ejection in quality at the upper sternal border; may sound more holosystolic at the lower sternal border
      • Presence of continuous murmur suggests presence of significant collaterals ^r5
    • May transmit widely, particularly to lung fields
    • Maximum intensity is usually at left upper sternal border
  • Early systolic ejection click may precede murmur
• Signs of heart failure (eg, tachypnea, rales, hepatosplenomegaly) are less common in infants but may be present in patients presenting outside of infancy ^{c14c15c16c17c18c19}
• Findings associated with long-standing cyanosis (eg, digital clubbing, dusky blue skin, grey sclerae with engorged blood vessels) are uncommon unless diagnosis is delayed until late childhood or adulthood ^{r5c20c21c22c23}
• Findings during paroxysmal hypercyanotic attacks may include:
  • Acute increase and progressive worsening of cyanosis
  • Murmur disappears or decreases in intensity as flow across right ventricular outflow tract diminishes ^r5
  • Severe spells may progress to convulsions or hemiparesis ^r5

Associated congenital anomalies

• Other associated cardiac defects are variable and may include: ^r5
  • Anomalies of the aortic arch
    • Right-sided aortic arch in about 20% of cases ^r5
  • Anomalies of the pulmonary arteries
    • Including absence of branch pulmonary artery, often on the left and associated with ipsilateral pulmonary hypoplasia
  • Coronary artery anomalies in 5% to 14% of patients ^r7
  • Patent ductus arteriosus and atrial septal defects
  • Multiple ventricular septal defects
  • Complete atrioventricular septal defect
    • Often in association with Down syndrome
  • Congenital absence of pulmonary valve
    • Often with a distinct presentation associated with upper airway obstruction secondary to aneurysmal dilation of pulmonary arteries, resulting in bronchial compression
  • Incidental persistence of left superior vena cava draining into coronary sinus is common but not clinically significant
  • Aorticopulmonary collaterals
• Associated congenital syndromes, such as:
  • 22q11.2 deletion spectrum
    • DiGeorge syndrome
    • Shprintzen velocardiofacial syndrome (CATCH 22 syndrome: cardiac defects, abnormal facial features, thymic hypoplasia, cleft palate, and hypocalcemia)
  • Down syndrome (trisomy 21)
  • Trisomy 13 and 18
  • Alagille syndrome

Causes

• Exact mechanism is unknown^r1, but maldevelopment of the embryonic conotruncus is suspected, which is associated with genetic disorder ^c24c25

Risk factors and/or associations

Primary diagnostic tools

• Clinical history and physical examination, typically in a neonate, raise suspicion for the diagnosis ^c43
• Chest radiography should follow as initial imaging in all suspected cases
• ECG is done in patients with suspected congenital heart disease as well as part of the assessment after repairs to detect any potential dysrhythmias
• Echocardiography confirms the diagnosis
• In adults, cardiac MRI is the gold standard imaging modality for quantification of right ventricular size and function in patients with repair; useful to quantify ventricular size and function, pulmonary valve function, pulmonary artery anatomy, and left-sided heart abnormalities in patients with repair ^r10
• Laboratory tests that assess oxygenation status, including arterial blood gas analysis and pulse oximetry, may be useful in the management of patients with moderate to severe cyanosis

Laboratory

• Pulse oximetry ^c44
• Arterial blood gas measurement ^c45
  • Establishes oxygenation status and detects metabolic acidosis

Imaging

• Plain chest radiography ^c46
  • Obtain in all patients with suspected congenital heart disease
  • Classic findings in anteroposterior view include:
    • Boot-shaped cardiac silhouette with prominent right ventricle ^r5
      • Upturned apex reflects right ventricular hypertrophy
      • Concavity at upper left heart border in area usually occupied by pulmonary arteries
      • Narrow base
      • Otherwise, normal heart size overall
    • Diminished overall pulmonary vascularity
    • Clearer than normal hilar areas secondary to diminished pulmonary blood flow and/or small pulmonary arteries
    • Aorta
      • Caliber is usually large
      • Aorta arches to the right in about 20% of patients, resulting in indentation of the leftward-positioned tracheobronchial shadow ^r5
• Echocardiography ^c47
  • Obtain in all patients with suspected congenital heart disease to confirm diagnosis
  • Common findings include ventricular septal defect(s), obstruction of right ventricular outflow tract, and anomaly of right-sided aortic arch ^r9
  • Transthoracic 2-dimensional echocardiography with color flow Doppler imaging ^r8
    • Used in most patients to assess structural and physiologic information
  • Transesophageal echocardiography ^r8
    • May be used preoperatively or intraoperatively
• Cardiac MRI ^r11r12c48
  • Provides information to decide if/when repair or reoperation is necessary
    • Localizes and quantifies pulmonary/systemic blood flow through a ventricular septal defect
    • Assesses right ventricular function and outflow tract obstruction
    • Measures pulmonary regurgitation or stenosis ^r11
    • Detects fibrosis of right ventricular muscle
    • Documents stenosis in distal pulmonary artery bed
  • In adults, useful to quantify ventricular size and function, pulmonary valve function, pulmonary artery anatomy, and left-sided heart abnormalities in patients with repair ^r10
• CT ^r11c49
  • Provides anatomic information to decide if/when repair or reoperation is necessary
  • Mostly used in patients for whom MRI is contraindicated (eg, patient has metal implants)
  • Disadvantages include need for ionizing radiation and iodinated contrast material

Functional testing

• ECG ^c50
  • Obtained in patients with suspected congenital heart disease
  • Done as part of assessment after repairs to detect any potential dysrhythmias
  • Interpretation
    • Common findings include: ^r1
      • Right axis deviation
      • Evidence of right ventricular hypertrophy
        • Upright T wave in V₃R and V₁ ^r5
        • Dominant R waves in the anterior precordial leads (eg, Rs, R, qR, qRs) ^r5
        • Large S waves in the lateral precordial leads
      • Right atrial enlargement (eg, tall, peaked T waves in V₁) ^r5
    • QRS complex prolongation greater than 180 milliseconds shows propensity for sustained ventricular tachycardia and sudden cardiac death ^r13
  • Exercise testing ^r14c51
    • Used to detect exertional arrhythmias and assess functional work capacity
    • Typically performed in long-term evaluation of patients after corrective surgery of tetralogy of Fallot

Procedures

Most common

• Isolated ventricular septal defect ^c54d1
  • Distinguishing features
    • Ventricular septal defect is the most common congenital cardiac defect; increased pulmonary pressures are noted
    • Characterized by a hole in the intraventricular septum, typically resulting in shunting of blood from left to right ventricle
  • Differentiating tests
    • Chest radiography does not show the classic boot-shaped heart visualized in tetralogy of Fallot
    • Echocardiography is the definitive study; it shows a septal defect but does not show other identifying characteristics of tetralogy of Fallot (eg, pulmonary stenosis, right ventricular hypertrophy, overriding aorta)
• Pulmonary atresia with intact ventricular septum ^c55
  • Distinguishing features
    • Deficiency of development of pulmonary valve or infundibulum and atretic right ventricular outflow tract
    • Cardiac auscultation reveals a single loud second heart sound, which is similar to tetralogy of Fallot; unlike tetralogy of Fallot, however, there are no audible murmurs
  • Differentiating tests
    • Echocardiography is the definitive study and shows severe right ventricular hypertrophy; however, it does not show other identifying characteristics of tetralogy of Fallot (eg, pulmonary stenosis, overriding aorta)
• Patent ductus arteriosus ^c56
  • Distinguishing features
    • Abnormal persistence of blood vessel between aorta and pulmonary artery after birth; left to right shunting of blood occurs when pulmonary vascular resistance has diminished
    • Commonly associated with hypoxia and prematurity
    • Tachycardia and exertional dyspnea may be present
  • Differentiating tests
    • Chest radiography shows prominent pulmonary vasculature but does not show classic boot-shaped heart visualized in tetralogy of Fallot
    • Echocardiography is the definitive study
• Aortic stenosis ^c57d2
  • Distinguishing features
    • As degree of stenosis increases, symptoms (eg, angina, dyspnea, fatigue, syncope)—particularly on exertion—may develop
    • Rarely symptomatic in children younger than 5 years
    • Systolic heart thrills may be palpable at base of heart, in jugular notch, and along carotid arteries
  • Differentiating tests
    • Echocardiography is the definitive study; it shows stenotic aortic valve and possible left ventricular hypertrophy but shows no other identifying characteristics of tetralogy of Fallot (eg, pulmonary stenosis, right ventricular hypertrophy, overriding aorta)

Admission criteria

Recommendations for specialist referral

• Transport neonates and infants suspected of having or diagnosed with tetralogy of Fallot to a medical center equipped to evaluate and manage complex congenital heart disease
• Refer children with cyanotic heart disease to a pediatric cardiologist for further evaluation
• After tetralogy of Fallot is diagnosed, refer patient to a cardiothoracic surgeon (who has expertise in congenital heart disease) for surgical repair
• Adults who have undergone tetralogy of Fallot repair should have their cases managed in conjunction with a cardiologist (who has expertise in treating congenital heart disease) at least once per year

Drug therapy

• For neonates with severe right ventricular outflow obstruction
  • Alprostadil (prostaglandin E₁) ^c58
    • Administer at birth to maintain patent ductus in newborns and increase pulmonary blood flow. Continue infusion until neonate is transferred to a specialized center for surgical repair
    • Continuous IV or intra-arterial infusion
      • Alprostadil Solution for injection [Ductus Arteriosus Patency]; Neonates: 0.05 to 0.1 mcg/kg/minute continuous IV or intra-arterial (umbilical) infusion, initially. After a therapeutic response is achieved, reduce the dose to the lowest possible dose that maintains the response. Usual dose: 0.01 to 0.1 mcg/kg/minute. Max: 0.4 mcg/kg/minute.
      • Alprostadil Solution for injection [Ductus Arteriosus Patency]; Infants: 0.05 to 0.1 mcg/kg/minute continuous IV or intra-arterial (umbilical) infusion, initially. After a therapeutic response is achieved, reduce the dose to the lowest possible dose that maintains the response. Usual dose: 0.01 to 0.1 mcg/kg/minute. Max: 0.4 mcg/kg/minute.
    • Anticipate apnea with administration ^r5r20
• Stepwise protocol for treatment of hypercyanotic spells in infants or children ^r1r4
  • Morphine sulfate ^c59
    • Sedates the patient, relaxes the outflow tract of the right ventricle, and reduces ventilatory drive during hypercyanotic spells ^r1r4
    • Morphine Sulfate Solution for injection; Infants and Children: 0.05 to 0.1 mg/kg/dose IV/IM; may repeat dose as needed until desired response is achieved.
  • β-blockers ^c60
    • Relaxes the right ventricular outflow tract and improves pulmonary blood flow during acute episodes ^r4r21
    • Prophylactic treatment may prevent occurrence of cyanotic spells in preoperative patients (optimum dose unavailable) ^r21
    • Propranolol ^c61
      • Oral
        • Propranolol Hydrochloride Oral solution [Cardiovascular Disease]; Infants and Children: 1 mg/kg/day PO divided every 6 hours, initially. After 1 week, may titrate dose by 1 mg/kg/day every 24 hours as necessary. Average dose: 2.3 mg/kg/day (range: 0.8 to 5 mg/kg/day). Usual Max: 5 mg/kg/day. May further increase dose gradually if the patient becomes refractory after initial control. Max: 10 to 15 mg/kg/day. Alternatively, 4 mg/kg/day PO divided every 6 hours has been used as an initial dose.
      • Intravenous
        • Propranolol Hydrochloride Solution for injection; Infants and Children: 0.15 to 0.25 mg/kg/dose (Max: 1 mg/dose) IV; may repeat once. Alternatively, 0.01 to 0.02 mg/kg/dose IV has been used, reserving higher doses for refractory spells.
  • Phenylephrine ^c62
    • Increases systemic vascular resistance, improves right ventricular outflow, and decreases right to left shunting ^r5
    • Phenylephrine Hydrochloride Solution for injection; Neonates: 5 to 20 mcg/kg/dose IV once, followed by 0.1 to 5 mcg/kg/minute continuous IV infusion.
    • Phenylephrine Hydrochloride Solution for injection; Infants and Children: 5 to 20 mcg/kg/dose IV once, followed by 0.1 to 5 mcg/kg/minute continuous IV infusion.

Nondrug and supportive care

Paroxysmal hypercyanotic spell

• Calm and hold infant ^r5
• Place patient in knee-to-chest position ^r5
  • Ensure that patient’s clothing is not restrictive
• Administer oxygen with goal to increase oxygen saturation to more than 90% ^r4c63
  • Administration of oxygen does not reverse cyanosis caused by right to left intracardiac shunting
• Avoid premature attempts to obtain blood samples; may result in further agitation and worsening of hypercyanotic spell ^r5
• Administer medications in stepwise fashion, starting with morphine, if hypercyanotic spell does not appear to be reversing ^r5
• Unusually severe spells recalcitrant to stepwise medical therapy may require the following: ^r5
  • Sodium bicarbonate administration to treat resultant metabolic acidosis ^r4
    • Expect rapid recovery from spell once pH returns to reference range ^r5
  • Sedation and paralysis followed by intubation and mechanical ventilation
  • Emergent palliative systemic to pulmonary shunt or complete corrective surgery
• Definitive surgical treatment is indicated once paroxysmal hypercyanotic spells begin ^r5

Endocarditis prophylaxis ^r22r23r24

• Consider for dental procedures involving manipulation of gingival or periapical region of teeth or manipulation of oral mucosa ^r25
• Indicated for patients with: ^r26
  • Unrepaired cyanotic congenital heart disease
  • Repairs using prosthetic material during the first 6 months after corrective surgery
  • Prosthetic valves (including transcatheter valve) or prosthetic material used for valve repair
  • Residual defects at the site or adjacent to the site of prosthetic patch after corrective repair
  • Previous episodes of infective endocarditis

Sports participation ^r27

• All patients (repaired or unrepaired) require comprehensive assessment with clinical assessment, ECG, imaging (eg, echocardiography) to assess ventricular function, and exercise testing before participation in competitive sports
• Stable patients without corrective surgery and without clinical manifestations of heart failure
  • May consider low-intensity/class IA sports (eg, bowling, cricket, golf, yoga) ^r28
• After corrective surgery, patients without significant valvular dysfunction, outflow tract obstruction, and evidence of arrhythmia
  • May consider moderate/class II to high-intensity/class III sports ^r28
• After corrective surgery, patients with significant ventricular dysfunction, outflow tract obstruction, or recurrent or uncontrolled arrhythmia may not participate in any competitive sports

Comorbidities

• For conditions requiring dental procedure, bowel surgery, or bladder surgery, administer subacute bacterial endocarditis prophylaxis in patients with uncorrected tetralogy of Fallot
• Other coexisting cardiac abnormalities that may require a modified surgical approach
  • Persistent foramen ovale/atrial septal defect
  • Pulmonary artery anomalies
  • Persistent left-sided superior vena cava to coronary sinus anomaly
  • Additional ventricular septal defects
  • Coronary artery anomalies

Special populations

• Pregnant patients
  • Pregnancy is not advisable in patients with uncorrected tetralogy of Fallot without evaluation and risk assessment by a cardiologist
  • Pregnancy is generally well tolerated in women with repaired tetralogy of Fallot if significant hemodynamic abnormalities are not present before pregnancy ^r35
  • Offer fetal echocardiography given higher risk of congenital heart disease ^r9
  • Consider testing for 22q11.2 microdeletion, given higher risk in offspring born to mothers with conotruncal defects, when maternal status is unknown ^r36

At-risk populations

• Children with (1 or both) parents who have tetralogy of Fallot ^r9

Screening tests

• Universal newborn pulse oximetry at time of nursery discharge, to screen for occult hypoxia that may be associated with congenital heart disease, is recommended ^r48r49c83
  • Screening protocol algorithms are available ^r49
• Screen for chromosomal band 22q11.2 microdeletion before pregnancy in patients who have conotruncal cardiac abnormalities; provide appropriate genetic counseling ^r9c84
• Offer fetal echocardiography in the second trimester to pregnant patients with conotruncal abnormalities to screen for fetal abnormalities, such as ventricular septal defect and aortic septal override ^r9c85