Tetralogy of Fallot

Introduction

• TOF is the most common form of cyanotic CHD, estimated to represent 5-10% of all CHD malformations.^1,2 First described by French doctor Louis Arthur Etienne Fallot in 1888, it is comprised of a tetrad of lesions: an interventricular communication or VSD, the aorta overriding the crest of the ventricular septum, (RVOTO; mainly infundibular pulmonary stenosis [PS]), and RVH.^1,3
• TOF with PS is the most common form of TOF. There are other anatomical variations that make up a small percentage of patients with TOF:
  • TOF with Pulmonary Atresia: 5-10% of patients with TOF. The pulmonary valve is atretic, allowing no antegrade pulmonary blood flow across the right ventricular outflow tract. There is a wide anatomical spectrum ranging from isolated valvar membranous atresia to muscular long-segment infundibular atresia. The pulmonary arteries also vary widely in morphology, from hypoplastic or stenotic to discontinuous or absent. Pulmonary blood flow is dependent on a patent ductus arteriosus (PDA) or on major aortopulmonary collateral arteries (MAPCAs).^1-3
  • TOF With Absent Pulmonary Valve: 3-6% of patients with TOF. The pulmonary valve leaflets are rudimentary, allowing free pulmonary regurgitation with a resultant massive aneurysmal dilation of the main and branch pulmonary arteries, sometimes leading to external airway compression and tracheobronchomalacia.^1,2
  • TOF With Common Atrioventricular Canal: in 2-3% of patients with TOF and is more commonly associated with trisomy 21.^1,2
• For the purposes of this summary, TOF refers to tetralogy of Fallot with PS (TOF/PS or simply TOF).

Anatomy

TOF consists of 4 major components: VSD, RVOTO, overriding aorta, and RVH (Figure 1).

VSD

• Results from anterior malalignment of the conal septum relative to the ventricular septum, hence the term “conoventricular.”^1,2
• VSD is typically large and unrestrictive, allowing equalization of pressure between the left and right ventricles. Additional VSDs may be present as well.^1,4
• Rarely, the VSD can be restrictive, either because of small size or, more commonly, because tricuspid valve tissue impinges into the defect.^2,4

RVOTO

• RVOTO is multilevel and multifactorial.^1,2,4
• The pulmonary valve is often bicuspid with thick leaflets, and the annulus is hypoplastic, leading to stenosis at the pulmonary valve level.^1,2
• An anteriorly malaligned VSD results in the conal septum protruding into the RVOT, crowding the infundibular region. This is exacerbated by the progression of the RV hypertrophy.^2,4
• A supravalvular component at the sinotubular junction is often present as well.^1,4

RVH^1,2,4

• RVH is due to the large VSD and RVOT obstruction.
• RV wall thickness can progress with time.

Overriding of the Aorta^1-3

• Due to displacement of the malaligned outlet septum into the RV, the aortic root overrides the ventricular septum, receiving blood from both ventricles.

Etiology

Embryology

• TOF results from abnormal development of the conotruncal (outflow tract) region during weeks 3-8 of embryogenesis.^1,2,4
• Normally, the conotruncus spirals and separates into two equal-sized great vessels, ensuring proper connections of the aorta and pulmonary artery with their respective ventricles.² In TOF, anterocephalad displacement of the infundibular septum leads to malalignment between the ventricular septum and the aortic root, resulting in VSD, RVOTO, overriding aorta, and eventually RVH.^1,2,4

Genetic Factors

• 20-25% of patients with TOF have associated genetic abnormalities, either as single gene mutations or as part of chromosomal syndromes.^1,2
• The most common association is 22q11.2 deletion syndrome (velocardiofacial or DiGeorge syndrome), which is present in 15% of patients with TOF (though it is more commonly associated with TOF with pulmonary atresia).^1,2,4
• TOF is associated with Trisomy 21, 13, and 18.^1,2,4
• Other gene mutations linked with TOF include:^2,4
  • GATA4 gene mutations, mainly associated with septal defects
  • JAG1 gene mutation associated with Alagille syndrome, which carries a high incidence of TOF
  • TBX5 gene mutation found in Holt-Oram syndrome
  • FOXC2 gene mutation in hereditary lymphedema-distichiasis syndrome
• As with other types of CHD, TOF has a familial recurrence rate of 2–4% in siblings and a higher transmission rate in offspring of affected parents.^2,4

Epigenetic factors

• Associations with maternal exposure to retinoic acid and other teratogens, as well as with folate deficiency or maternal diabetes, have been described.

Associated Anomalies

• Additional muscular VSDs are present in 5% of patients.^1,2
• Atrial septal defect (ASD)^1,2
• Right aortic arch with mirror image branching is present in 25% of patients.^1,2
• Anomalous origin of the coronary arteries is present in 5-10% of patients. This is most commonly an anomalous origin of the left anterior descending artery from the right coronary artery, often crossing the RVOT, posing a surgical risk in case of infundibulotomy.^1-4 The delineation of the coronary anatomy is thus crucial for surgical planning.

Pathophysiology

• The VSD, typically large and unrestrictive, plays a minor role in influencing the direction of the shunt, with the shunt direction depending on the SVR and PVR.^1,4
• The main determinant of TOF symptoms is the degree of RVOTO, which has both fixed and dynamic components:
  • Fixed component: due to pulmonary valve and annular hypoplasia, as well as crowding of the infundibular region secondary to ventricular septum malalignment. This can worsen over time, and if the RVOTO exceeds the SVR, a right-to-left shunt occurs across the VSD, leading to cyanosis even at rest.^1,2,4
  • Dynamic component: involves the muscular component of the RVOT and can worsen with progressive RVH. The dynamic obstruction or subpulmonary infundibular “spasm” is worsened by increased catecholamines, as well as by increased PVR or decreased SVR.^4,5
• “Pink Tet”: In patients with mild RVOTO, the shunt is mainly left to right, leading to pulmonary overcirculation and heart failure symptoms.^1,4

Hypercyanotic Spell

• A hypercyanotic spell (“Tet spell”; Figure 2) occurs when dynamic infundibular spasm compounds fixed RVOT obstruction, leading to further decrease in pulmonary blood flow and worsening cyanosis.
• Infundibular spasm is worsened by increased catecholamines (agitation, crying, pain, dehydration, exogenous beta agonist administration), but can also occur spontaneously.^4,5
• Spells can also be triggered by reductions in SVR (vasodilating drugs, sepsis/infection, warm external environment).
• The frequency of spells increases with age, and they are most common in infants 2-4 months old. For unclear reasons, however, they are rare in unrepaired adults.
• Cyanosis improves with maneuvers that increase SVR and decrease PVR.
• Spells can be self-limited or resolve with intervention. Severe cases can progress to syncope, seizures, neurologic injury, or death.

Diagnosis

Clinical Presentation

• With the advances in fetal echocardiography, TOF is often diagnosed in utero.^1,4,6
• The hallmark clinical manifestation of TOF is cyanosis, the severity of which depends on the degree of RVOTO. Cyanosis usually worsens with age as well as during exertion, such as agitation, crying, and feeding. Many infants remain well despite cyanosis, with no respiratory distress or feeding difficulties.^1,2,4
• On auscultation, a harsh, long, crescendo–decrescendo systolic ejection murmur is heard at the left sternal border. It is generated by the turbulent flow across the RVOT rather than across the VSD.1,2 During hypercyanotic spells, the murmur softens or disappears due to a decrease in pulmonary blood flow across the RVOT. The rest of the cardiovascular exam is usually unremarkable.^1,2,5,6
• Patients with mild PS are not cyanotic and exhibit signs of heart failure, including tachypnea, tachycardia, diaphoresis, poor oral feeding, and failure to thrive.^1,4

Diagnostic Studies

• Pulse Oximetry (SpO₂): confirms cyanosis. Persistent resting SpO_₂ < 80–85% usually warrants a surgical intervention, and a decrease in SpO₂ below 65-70% is an indication for urgent surgery.^1,4
• Electrocardiography (ECG): May be normal at birth. With time, RVH, right-axis deviation, and right atrial enlargement develop.^1,2 In “Pink TOF” with a large left-to-right shunt, left atrial enlargement may develop.^1,2
• Chest X-ray (CXR): typically shows a normal heart size with decreased pulmonary vascularity, and in 25% of cases, a right aortic arch. The classic “boot-shaped heart” (Figure 3) is often seen, secondary to RVH and hypoplasia of the main pulmonary artery.^1,2,4,6 In “pink TOF”, the heart is enlarged with increased pulmonary vascularity.

• Echocardiography: Prenatal diagnosis can be made via fetal echocardiogram as early as 11-12 weeks of gestation. Postnatally, an echocardiogram is the mainstay diagnostic tool for defining the VSD, pulmonary artery size, and RVOT and coronary artery anatomy.^1-3,6
• Cardiac Catheterization: is rarely indicated in TOF with PS, but is indicated in patients with pulmonary atresia and MAPCAs.^3,4
• Magnetic Resonance Imaging (MRI): can provide detailed anatomical and functional data but is rarely needed preoperatively. It is a vital tool for evaluation of older patients after surgical repair of TOF to assess RV size and function as well as the degree of pulmonary regurgitation, and to guide therapeutic options and their timing.^1,4
• Cardiac Computed Tomography (CT): Rarely used preoperatively, except when the coronary artery anatomy is not clearly delineated by echocardiogram. It is also an alternative to MRI in older patients with repaired TOF who have a pacemaker or implanted defibrillator.^1,4

Treatment Strategies

Medical Management

• In rare cases where pulmonary blood flow is ductal-dependent, a continuous infusion of prostaglandin E1 is required to maintain ductal patency. This is more relevant in TOF with pulmonary atresia rather than with PS.^3,4
• Management of Hypercyanotic Spells: The treatment goals are to relieve infundibular spasm, increase SVR, decrease PVR, and optimize RV preload and pulmonary blood flow:
  • Calm and soothe the child to reduce endogenous catecholamines.
  • Consider administering sedation (e.g., morphine, ketamine).
  • Mechanically increase SVR by placing the patient in the knee-chest position (older, unrepaired children will classically squat) or applying abdominal or direct aortic compression.
  • Administer a fluid bolus to increase preload and pulmonary blood volume.
  • Alpha-agonists to increase SVR in refractory spells:
    • Phenylephrine 5-10 mcg/kg intravenous (IV) bolus, or infusion, and titrate to effect.
  • Beta-blockers to relieve infundibular spasm (with clinical and vital signs monitoring):
    • Propranolol (commonly used): 0.1 mg/kg, given slowly
    • Esmolol (short-acting, faster onset): 50-200 mcg/kg, and titrate to effect
  • Provide supplemental oxygen to decrease PVR.
  • Intubation, mechanical ventilation, and deep sedation may be required for severe, refractory, or decompensating spells.
• Pink TOF: Depending on the degree of PS, patients with pink TOF might follow the trajectory of patients with a simple VSD, with signs of heart failure manifesting in the neonatal period or soon after. Diuretics and anti-congestive medications may be indicated.^1,4,6

Interventional Management

• Interventional catheter-based palliation is rarely used today, except in the rare instances where a definitive surgical repair is contraindicated or deferred. This includes balloon dilation or stenting of the RVOT, or ductal stenting to maintain pulmonary blood flow.^1,4

Surgical Management

• Early complete repair in infancy is now performed by most institutions. The age of elective repair has been declining and is now between 1 and 3 months of age for asymptomatic infants or earlier in the case of recurrent or profound cyanosis.^1,3,4
• In rare cases where a definitive surgical repair is contraindicated or deferred, surgical palliation may be performed using a modified Blalock-Taussig-Thomas shunt (polytetrafluoroethylene graft interposed between the subclavian artery and the ipsilateral pulmonary artery).^3,4,6
• Surgical repair may be approached via a transatrial-transpulmonary approach in cases where the RVOTO is due to moderate muscle bundle hypertrophy rather than diffuse hypoplasia. The pulmonary valve and annulus are then serially dilated with Hegar dilators.^1,3
• Most repairs require a transventricular incision (infundibulotomy) with patch augmentation of the outflow tract, and/or valve annulus and pulmonary arteries:^1,3,4
  • Non-transannular (valve-sparing, two patch repair): if the annulus size is adequate (z score > -2.5), the incision stops below the pulmonary valve annulus, preserving the integrity of the pulmonary valve.
  • Transannular patch: If the annulus is hypoplastic, the incision extends across the pulmonary annulus and the anterior main pulmonary artery. This often sacrifices valve competence and leads to chronic pulmonary regurgitation, while avoiding the risk of residual PS.
• Surgical repair also includes resection of RV muscle bundles and VSD patch repair.
• Associated lesions (PDA, additional muscular VSDs, and ASDs) are closed as indicated.^1,3
• A small fenestration may be created in the atrial septum or a patent foramen ovale left open to allow for right-to-left atrial level shunting in the setting of restrictive RV physiology in the early postoperative period.^1,3

Anesthetic Considerations for Interventional/Surgical Management

Preoperative Evaluation^4,5

Labs

• Complete blood cell count
• Type and crossmatch
• Basic metabolic profile, including renal function and electrolytes if the patient is on diuretics (usually for pink TOF), and glucose (if the patient is on propranolol)

Imaging/Diagnostics

• ECG, CXR
• Cardiac CT in patients where coronary artery anatomy is not clearly delineated by echocardiogram

Intraoperative Management

Monitoring^4,5

• Standard American Society of Anesthesiologists monitors
• Core temperature monitoring
• Near-infrared spectroscopy
• Invasive pressure monitoring – arterial pressure and central venous pressure
• Transesophageal echocardiography: to assess the surgical repair, including the pulmonary valve, RVOT, residual shunts, and ventricular function.

Access

• Two large-bore peripheral IV catheters
• Arterial line
• Central line

Anesthesia Technique

• General endotracheal anesthesia is typically used.
• Air bubbles must be avoided in the IV lines.

Hemodynamics Goals^4-6

• The hemodynamic goal in the pre-cardiopulmonary bypass period is to balance SVR and PVR to decrease cyanosis and maintain adequate oxygenation and cardiac output. This is a high-risk period, even in previously stable patients, as the combination of a prolonged NPO time with the induction of general anesthesia and the surgical stressors is the perfect recipe for precipitating cyanotic spells.
• NPO time should be kept to a minimum. Some advocate placing an IV catheter preoperatively to allow IV fluid administration. Avoid hypovolemia.
• Avoid agents that lower SVR (propofol, high-dose volatile anesthetics, morphine in patients under general anesthesia). Ketamine is a popular choice for the induction of general anesthesia as it increases SVR.
• Avoid an increase in PVR by avoiding hypercarbia, hypoxemia, acidosis, and hypothermia.
• Avoid beta-agonists (dopamine, epinephrine) as they can worsen infundibular spasm.
• Use alpha agonists (phenylephrine or norepinephrine) or vasopressin to increase SVR.
• Increase FiO₂ and optimize ventilation to decrease PVR. Beware of high peak airway pressures and aggressive ventilation that can lead to auto-positive end-expiratory pressure and result in increased intrathoracic pressures, decreased venous return, and increased PVR.
• Ensure an adequate depth of anesthesia and analgesia to avoid a surge in endogenous catecholamines and an ensuing infundibular spasm.
• Treat hypercyanotic spells (as above). In refractory cases, urgent cannulation to extracorporeal membrane oxygenation (ECMO) or cardiopulmonary bypass.
• Early extubation is desirable, as it improves preload and RV filling.

Postoperative Care

The early postoperative course after TOF repair may be complicated by RV dysfunction, residual VSD, and arrhythmias:

• RV Dysfunction:^1,5,6
  • RV hypertrophy can limit myocardial protection during aortic cross-clamping. In addition, muscle band resection and placement of a large VSD patch contribute to poor RV compliance and diastolic dysfunction.
  • Management strategies vary, with some advocating beta-blockers and avoiding beta-agonists to support blood pressure with fluids and vasopressors, while others caution against liberal fluid loading. Most cases are transient, but persistent dysfunction warrants investigation for surgically correctable lesions.
• Residual VSD:³ Closure may be technically challenging in hypertrophied ventricles. Subaortic defects carry the risk of heart block and arrhythmia.
• Arrhythmias:
  • Junctional ectopic tachycardia: Occurs in 15–20% of patients postoperatively, leading to hypotension, low cardiac output, and hemodynamic instability.^5,6
  • Risk factors: age <6 months, postoperative dopamine use.
  • Management: correction of electrolytes, hypothermia, reduction of inotropes, atrial pacing to restore AV synchrony, sedation/analgesia (dexmedetomidine), magnesium, antiarrhythmics (amiodarone, procainamide, esmolol). ECMO may be required in refractory cases.⁵
  • Conduction abnormalities: RBBB is common; bifascicular block occurs in 8–12%, and complete AV block in 3–5%.^1,5
  • The transatrial-transpulmonary approach leads to fewer tachyarrhythmias and lower pacemaker requirements than a transventricular approach.^3,5
• Persistent RV compromise, significant arrhythmia, or unexplained hypoxemia should trigger detailed reassessment to exclude residual lesions or injury to the conduction system.^3,5