Tetralogy of fallot

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Tetralogy of Fallot (TOF)

Definition & Epidemiology

Tetralogy of Fallot is the most common cause of cyanotic congenital heart disease beyond infancy, accounting for approximately 5% of all congenital cardiac malformations. It is defined by four structural abnormalities that all arise from a single embryologic defect.

Robbins & Kumar Basic Pathology, p. 273
Rosen's Emergency Medicine, p. 3210

The Four Cardinal Features

Feature	Details
1. Right ventricular outflow tract (RVOT) obstruction	Usually subpulmonic (infundibular) stenosis; can be valvular or complete atresia
2. Ventricular septal defect (VSD)	Large, unrestrictive, misaligned defect near the membranous septum
3. Overriding aorta	Aortic valve straddles the VSD, receiving blood from both ventricles
4. Right ventricular hypertrophy (RVH)	Secondary to high pressure load from RVOT obstruction

Embryologic Basis

All four features result from a single embryologic error: anterosuperior displacement of the infundibular septum (failure of subpulmonic conus to expand), leading to abnormal septation between the pulmonary trunk and the aortic root. In essence, unequal division of the truncus arteriosus results in a small pulmonary trunk and large aortic root.

The Developing Human, p. 847
Robbins & Kumar, p. 283

Anatomy & Morphology (Robbins)

Classic Tetralogy of Fallot - heart diagram showing RV, LV, RA, LA, PT (hypoplastic), and overriding Ao with right-to-left shunt arrow

Classic Tetralogy of Fallot: note the hypoplastic pulmonary trunk (PT), enlarged right ventricle (RV), and the overriding aorta (Ao). Arrow shows right-to-left blood flow across the VSD.

Heart is enlarged and boot-shaped on CXR (coeur en sabot) due to RVH
Proximal aorta is dilated; pulmonary trunk is hypoplastic
Left-sided chambers are normal in size
RV wall is markedly hypertrophied, sometimes exceeding LV thickness
In severe cases with pulmonary atresia, pulmonary blood flow depends entirely on a patent ductus arteriosus (PDA) or bronchial collateral vessels

Pathophysiology & Hemodynamics

The RVOT obstruction + large VSD produces a right-to-left shunt, meaning deoxygenated blood is ejected from the RV directly into the systemic circulation via the overriding aorta. This results in:

Decreased pulmonary blood flow
Increased aortic volume (mixed oxygenated/deoxygenated blood)
Systemic hypoxemia and cyanosis

The severity of shunting depends on: degree of RVOT obstruction + VSD size + systemic vascular resistance (SVR).

Rosen's Emergency Medicine, p. 3210

Clinical Features

Cyanosis Spectrum

"Pink Tet" (acyanotic): mild RVOT obstruction → left-to-right shunt predominates → no cyanosis at birth; gradually develops cyanosis by 1-3 years
Cyanotic TOF: severe RVOT obstruction → profound cyanosis within days of life; may require prostaglandin E1 (PGE1) infusion to keep PDA open and maintain pulmonary blood flow

Signs & Symptoms

Cyanosis (variable degree) - worsens with crying, feeding, exertion
Systolic ejection murmur along the left sternal border (from RVOT obstruction, not the VSD)
Clubbing of fingers and toes (from chronic hypoxemia)
Compensatory polycythemia (from chronic hypoxemia)

Associated Anomalies

Right-sided aortic arch (25% of cases)
ASD
Anomalous origin of the left coronary artery

Investigations

Investigation	Findings
CXR	Boot-shaped heart (coeur en sabot), decreased pulmonary vascular markings, concave main pulmonary artery segment, possible right-sided aortic arch
ECG	Right ventricular hypertrophy, right axis deviation
Echocardiography	Defines all four features; assesses degree of RVOT obstruction, coronary anatomy
Cardiac catheterization	Used pre-operatively in complex cases

Tet Spells (Hypercyanotic / Hypoxic Spells)

These are potentially life-threatening acute events, most common between 2-4 months of age.

Triggering Mechanism

Any event that acutely lowers SVR (crying, defecation) or causes hypovolemia/tachycardia initiates a vicious cycle:

Tet spell pathophysiology flowchart: acute SVR decrease leads to increased R-to-L shunting, then metabolic acidosis, then hyperpnea, then increased venous return, which further worsens shunting in a loop

Vicious cycle of a hypoxic (tet) spell: falling SVR increases R-to-L shunting → metabolic acidosis → hyperpnea → increased venous return to RV → more shunting

Clinical Features of Tet Spell

Hyperpnea, prolonged crying, worsening cyanosis
Murmur diminishes (less flow through RVOT, more through VSD)
Severe: limpness, seizures, CVA, or death

Management of Tet Spells

From Rosen's Emergency Medicine, Box 165.8:

Step	Intervention	Rationale
1st	Knee-to-chest position (infants) or squatting (older children)	Increases SVR, decreases R-to-L shunt
2nd	Supplemental oxygen	Limited benefit alone, but useful adjunct
3rd	Morphine 0.1-0.2 mg/kg IV/IM	Reduces hyperpnea, decreases sympathetic drive
Alt opioid	Fentanyl 1 µg/kg IV/IM or 1.5-2 mcg/kg intranasal	Alternative to morphine
Sedation	Midazolam 0.2-0.3 mg/kg intranasal	Reduces agitation
Acidosis	Sodium bicarbonate 1 mEq/kg IV	Corrects metabolic acidosis
Consider	Ketamine 1-2 mg/kg IV or 3-5 mg/kg IM	Increases SVR and provides sedation
Consider	Propranolol 0.1-0.2 mg/kg	Reduces infundibular spasm
Consider	Phenylephrine 0.01-0.02 mg/kg IV	Pure alpha-agonist - raises SVR directly

The three treatment goals are: (1) increase SVR, (2) abolish hyperpnea, (3) correct metabolic acidosis

Definitive Surgical Treatment

Primary surgical repair is the treatment of choice, ideally in early infancy
Involves VSD patch closure + RVOT reconstruction (infundibulectomy ± pulmonary valvotomy)
In severely symptomatic neonates, there is ongoing debate between primary repair vs. staged repair (palliative shunt first, then complete repair)
- A recent 2024 systematic review and meta-analysis (PMID 39444206) found no significant mortality difference between primary and staged repair in symptomatic neonates
In pulmonary atresia variant: a Blalock-Taussig (BT) shunt or other palliative shunt may bridge until complete repair
Del Nido cardioplegia vs. conventional blood cardioplegia is being studied; a 2025 meta-analysis (PMID 39757359) compared these approaches in TOF repair

Prognosis

Even untreated, some patients survive into adulthood (especially "pink tets")
With mild RVOT obstruction, presentation resembles an isolated VSD
Post-repair adults with TOF can develop late complications (RV dysfunction, pulmonary regurgitation, arrhythmias) and require ongoing surveillance with echocardiographic deformation imaging

Sources:

Robbins & Kumar Basic Pathology, pp. 273-284
Rosen's Emergency Medicine, pp. 3210-3211
The Developing Human: Clinically Oriented Embryology, p. 847
PMID 39444206 - Primary vs. staged repair meta-analysis (2024)
PMID 39757359 - Del Nido vs conventional cardioplegia meta-analysis (2025)

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