Tetralogy of Fallot

Embryologic Basis

• The fundamental defect originates from anterior-superior maldirection of the infundibular (conal) septum during weeks 4-8 of cardiac development
• This abnormal septation fails to separate the aorta from the right ventricle properly, resulting in concurrent VSD and aortic override
• The spectrum of RVOT obstruction (infundibular, valvular, or supravalvular) determines physiologic severity

Hemodynamic Consequences

• The VSD is typically large and non-restrictive, allowing equalization of RV and LV pressures; the degree of right-to-left shunting depends entirely on relative vascular resistance
• Right ventricular hypertrophy develops as a compensatory response to chronically elevated afterload from RVOT obstruction; RV pressure may exceed systemic pressure
• Overriding aorta (positioned >50% over the VSD) receives deoxygenated blood directly from the RV, delivering systemic hypoxemia
• The net shunt direction is determined by Qp:Qs ratio and relative resistances: when PVR < SVR, left-to-right shunting occurs ("acyanotic"); when RVP > systemic pressure due to RVOT obstruction, right-to-left shunting develops ("cyanotic")

"Tet Spell" Mechanism

• Acute increase in RVOT obstruction (infundibular muscle spasm, dynamic narrowing, or increased RV contractility) elevates RV pressure above aortic pressure
• This precipitates acute right-to-left shunting through the VSD, causing acute hypoxemia, cyanosis, and syncope
• Hyperventilation and increased sympathetic tone paradoxically worsen spells by increasing contractility and RVOT obstruction

Compensatory Mechanisms

• Polycythemia develops in response to chronic hypoxemia, increasing oxygen-carrying capacity but raising blood viscosity
• Increased 2,3-DPG in RBCs shifts the oxygen dissociation curve rightward, facilitating oxygen unloading at tissues
• Collateral bronchial circulation develops and may enlarge, visible on imaging

Genetic Factors

• Sporadic mutations account for ~85% of cases; familial inheritance (autosomal dominant with incomplete penetrance) occurs in ~15%
• 22q11 deletion (DiGeorge/CATCH-22 syndrome) present in 15-40% of TOF patients; associated with cleft palate, hypocalcemia, thymic hypoplasia, renal anomalies, and hearing loss
• Other genetic syndromes: Down syndrome (trisomy 21), Williams syndrome, Noonan syndrome, VATER association

Maternal Risk Factors

• Maternal diabetes (especially poorly controlled gestational or type 1 diabetes) increases risk 2-3 fold
• Maternal rubella infection during first trimester
• Fetal alcohol syndrome
• Maternal phenytoin or other anticonvulsant exposure
• Maternal lithium exposure (controversial association)

Idiopathic

• Majority of cases lack identifiable maternal or genetic risk factor

Neonatal/Early Infancy (Severe Cyanotic TOF)

• Cyanosis appearing within first hours to days of life, initially may improve with prostaglandin E1 (PGE1), which maintains the ductus arteriosus patent
• Severe hypoxemia with oxygen saturation typically 75-85%
• Tachypnea and poor feeding

Infantile/Childhood (Moderate-to-Severe TOF)

• Classic "tet spells" (hypercyanotic spells): acute onset of intense cyanosis, dyspnea, irritability, and syncope lasting minutes to hours
• Squatting position assumed by older children during spells—increases systemic vascular resistance, reduces right-to-left shunt, improves pulmonary blood flow
• Clubbing of fingers and toes from chronic hypoxemia
• Failure to thrive and poor exercise tolerance
• Cyanosis more prominent with crying or exertion

Physical Examination Findings

• Cyanosis (mild to severe depending on Qp:Qs ratio)
• Single S2 (due to anterior displacement of pulmonary valve)
• Boot-shaped heart visible on chest X-ray (coeur en sabot)
• Systolic ejection murmur at left upper sternal border from RVOT obstruction (NOT the VSD itself, as large VSDs are silent)
• Hepatomegaly if right heart failure develops
• Polycythemic facies—plethoric appearance with periorbital edema

Acyanotic Form ("Pink Tet")

• May present with left-to-right shunt and signs of pulmonary overcirculation
• Develops progressive cyanosis as RVOT obstruction worsens with age

Clinical Suspicion

• Cyanotic neonate or infant with "tet spell" characteristics
• History of squatting behavior
• Clubbing and polycythemia

Electrocardiography (ECG)

• Right axis deviation (RAD) with rightward QRS axis >+90° in children
• Right ventricular hypertrophy pattern: tall R wave in V1-V2, deep S wave in V5-V6
• Right atrial enlargement (tall P wave in II)
• Normal QTc interval (important to rule out long QT syndrome, another cause of sudden death)

Chest X-Ray

• Boot-shaped heart (coeur en sabot): combination of RV hypertrophy (creating rounded apex) and decreased pulmonary artery prominence
• Decreased pulmonary vascular markings ("oligemic lung fields") from reduced pulmonary blood flow
• Right aortic arch present in ~25% of cases (associated with 22q11 deletion)
• Cardiomegaly if right heart failure present

Echocardiography (Definitive Diagnostic Test)

• 2D echocardiography identifies the four cardinal features:
• Large VSD (typically perimembranous with anterior-superior maldirection)
• Overriding aorta (>50% origin from RV)
• RVOT obstruction with hypertrophied RV wall
• RV systolic pressure (calculated from tricuspid regurgitation jet by continuous-wave Doppler)
• Color Doppler demonstrates right-to-left shunting through VSD
• Allows assessment of associated lesions: atrial septal defect, patent foramen ovale, pulmonary stenosis severity, aortic arch anatomy

Cardiac Catheterization

• Indicated preoperatively to define coronary anatomy and assess collateral circulation
• Demonstrates: equal RV and systemic pressures, oxygen saturation step-up absent in aorta (right-to-left shunt), elevated Hgb in aorta vs. pulmonary artery
• Coronary angiography essential because anomalous left main coronary arising from right sinus of Valsalva occurs in 5-10% of TOF patients (relative contraindication to surgery without rerouting)

Cardiac MRI

• Increasingly used for anatomic assessment and assessment of RV function without radiation or contrast
• Useful in older children and adults

Laboratory Studies

• Hemoglobin and hematocrit: elevated (polycythemia with Hgb often 15-20 g/dL)
• Oxygen saturation: reduced (typically 75-85% SpO2 on room air in cyanotic TOF)
• Blood gases: low PaO2 with metabolic acidosis during severe spells
• Hypercoagulability studies: assess thrombosis risk in polycythemic patients

Diagnostic Criteria (Clinical)

• Cyanosis or hypoxemia with Qp:Qs <1:1
• Four cardinal anatomic features on imaging
• Exclusion of other cyanotic lesions (transposition of great arteries, tricuspid atresia, total anomalous pulmonary venous return, pulmonary atresia)

Medical Management (Acute Tet Spell)

• Immediate position: place child in knee-chest or squatting position to increase systemic vascular resistance
• Oxygen: 100% supplemental oxygen to reduce pulmonary vascular resistance and improve pulmonary blood flow
• Morphine: 0.1 mg/kg IV/IM to reduce infundibular contractility, anxiety, and RV outflow obstruction
• Beta-blockers (propranolol): 0.01-0.1 mg/kg IV to reduce RV contractility and RVOT obstruction severity; can be given prophylactically (0.25-1 mg/kg PO tid) to prevent spells
• Sodium bicarbonate: 1 mEq/kg IV for metabolic acidosis
• Avoid: agitation, crying, hyperthermia, dehydration (all increase contractility and worsen obstruction)

Medical Management (Chronic)

• Beta-blockers (propranolol, atenolol, metoprolol): first-line prophylaxis against tet spells; reduce infundibular contractility
• Avoid: positive inotropes, diuretics (worsen obstruction via decreased preload); careful with vasodilators
• Phlebotomy: if Hgb >18 g/dL and symptoms of hyperviscosity (headache, visual changes, thrombosis); maintain Hgb 16-18 g/dL
• Iron supplementation: to replace iron lost during phlebotomy
• Antibiotic prophylaxis: for subacute bacterial endocarditis (SBE) in cyanotic patients before prophylaxis period
• Maintain hydration: crucial to prevent thrombotic events in polycythemic patients
• Avoid strenuous exertion: until corrective surgery

Prostaglandin E1 (PGE1) - Neonatal Management

• Maintains patent ductus arteriosus (PDA), allowing right-to-left ductal shunt to deliver oxygenated pulmonary venous blood to systemic circulation
• Improves SpO2 from ~60% to ~80-85%
• Dose: 0.05-0.1 mcg/kg/min IV infusion; titrate to maintain ductal patency
• Goal: bridge to surgical intervention
• Side effects: apnea (50%), fever, hypotension, seizures

Surgical Management (Definitive Treatment)

• Balloon atrial septostomy (Rashkind procedure): creates ASD to improve mixing; provides temporary palliation in critically cyanotic neonates
• Modified Blalock-Taussig shunt (BT shunt): anastomoses subclavian or innominate artery to pulmonary artery to increase pulmonary blood flow; palliative procedure (not curative) used if primary repair delayed or anatomic factors preclude early repair

• Definitive primary repair: preferred approach in most centers for infants >3 months or >5 kg
• VSD closure with patch
• RVOT obstruction relief: infundibular resection, pulmonary valve commissurotomy, removal of obstructing bands
• Transannular patch if severe pulmonary stenosis requires widening of RVOT (risks pulmonary regurgitation)
• Success rate >95% with mortality <1% in specialized centers
• Can be performed via median sternotomy with cardiopulmonary bypass

Late Surgical Decisions

• Pulmonary valve replacement: may be needed 10-20 years postoperatively if severe pulmonary regurgitation and RV dilation develops
• Arrhythmia surgery: mapping and ablation if atrial fibrillation or ventricular tachycardia develops
• RV outflow tract reintervention: occasionally needed if restenosis occurs

Immediate Perioperative

• Hemorrhage and coagulopathy
• Arrhythmias (especially atrial fibrillation postoperatively)
• Right ventricular dysfunction from ventriculotomy
• Pulmonary regurgitation (especially if transannular patch used)

Acute Medical

• Tet spell with syncope and risk of stroke from paradoxical embolism or hypoxic brain injury
• Thromboembolism: due to polycythemia, dehydration, and decreased cardiac output; increased risk of cerebral venous sinus thrombosis and stroke
• Cerebral abscess: via paradoxical embolism or bacteremia with right-to-left shunt
• Endocarditis: risk in cyanotic patients; presents with fever, new murmur, embolic phenomena
• Hypertensive crisis during spells

Late Complications (Post-Repair)

• Residual VSD: occurs in 5-10% of cases; may require reintervention
• Pulmonary regurgitation (PR): develops in 90% of patients with transannular patches; chronic PR leads to progressive RV dilation
• Atrial fibrillation: in 10-15% of adults; increases stroke risk
• Ventricular arrhythmias: from RV scar; risk of sudden cardiac death
• RV dysfunction and heart failure: from chronic volume overload (PR) or pressure overload
• Infective endocarditis: even postoperatively in residual defects
• Exercise intolerance: from chronotropic incompetence, arrhythmias

Management of Complications

• Tet spell: oxygen, morphine, beta-blockers, fluids, calcium channel blockers
• Stroke: urgent imaging (CT/MRI), anticoagulation/antiplatelet therapy, neurology consultation
• Endocarditis: antibiotics (culture-directed), surgical intervention if vegetation with embolization
• Arrhythmias: antiarrhythmic therapy (beta-blockers, amiodarone), pacemaker/ICD if indicated
• RV dysfunction: ACE inhibitors, beta-blockers, consideration of pulmonary valve replacement if severe PR with RV dilation

Natural History (Without Surgical Repair)

• Historically, 50% mortality by age 1 year if untreated
• Median age of survival in untreated severe TOF approximately 3 years
• Death from hypoxic events, arrhythmias, or complications (abscess, endocarditis)

Post-Operative Outcomes

• Excellent long-term survival: >95% at 10 years post-repair in contemporary series
• Quality of life: most repaired patients have normal or near-normal functional capacity
• Late reoperation rate: 10-15% require pulmonary valve replacement or other intervention within 20 years

Prognostic Factors

• Age at repair: earlier repair (infants vs. older children) associated with better outcomes
• Presence of 22q11 deletion: associated with additional cardiovascular lesions and increased comorbidities, but does not preclude good surgical outcomes
• Coronary anatomy: anomalous coronary origin does not absolutely preclude repair but

The stem's giveaways

• Four defects, one embryologic cause: pulmonary (RVOT) stenosis, RVH, overriding aorta, VSD — all from anterosuperior deviation of the infundibular septum. Only the degree of RVOT obstruction determines cyanosis; the VSD is large and non-restrictive, so it contributes no murmur.
• The murmur is the pulmonic stenosis murmur: a harsh systolic ejection murmur at the left upper sternal border with a single S2. During a tet spell the murmur gets softer or disappears (less flow across the RVOT). A stem describing a quieter murmur in a bluer child is describing worsening obstruction, not improvement — a classic distractor.
• Boot-shaped heart (coeur en sabot) with decreased pulmonary vascular markings; ECG shows right axis deviation and RVH. A right aortic arch raises suspicion for 22q11.2 deletion — the single association examiners test most (hypocalcemic seizures, absent thymus, cleft palate).

Best next steps

• Acute tet spell: the first maneuver is knee-chest positioning (raises SVR, reversing the right-to-left shunt), then oxygen, then an opioid (morphine) and a beta blocker (propranolol) to relax the infundibulum. Never give an inotrope, a diuretic, or a vasodilator — each worsens the shunt.
• Diagnostic test of choice is transthoracic echocardiography, not catheterization; cath is reserved largely for coronary anatomy before repair.
• Cyanotic neonate before surgery: prostaglandin E1 keeps the ductus open. Watch for apnea.

Long-game pearls

• Chronic hypoxemia causes secondary erythrocytosis with iron deficiency — relative anemia with normal-appearing hemoglobin is the trap; right-to-left shunting also permits paradoxical embolism and brain abscess.
• Post-repair adults: the dominant late lesion is severe pulmonary regurgitation after a transannular patch, driving RV dilation; the 2018 AHA/ACC adult congenital heart disease guideline supports pulmonary valve replacement in this setting. Marked QRS prolongation and ventricular tachycardia flag sudden-death risk.
• Endocarditis prophylaxis (AHA) applies to unrepaired cyanotic disease, the first six months after prosthetic-material repair, and residual defects adjacent to patch material — not to every repaired patient.