Incidence, anatomy, and natural history

Although EA occurs in only 0.3–0.7% of CHD, it is the most common congenital malformation of the tricuspid valve (TV) [1]. The incidence is approximately 1/10,000 live births [2]. EA was first described by Ebstein in 1866 [3] from necropsy findings. Clinical diagnosis was not achieved until 1949 [4] because the clinical presentation of more severe cases with diminished PBF and cyanosis resembled TOF, and partial competence of the malformed TV often was enough to prevent signs of CHF until late in evolution of the disease [5]. EA is characterized by a malformed TV and RV [6] (Table 28.1). With advent of cardiac catheterization and echocardiography, cardiologists were much more able to diagnose EA with certainty.

The highly varied range of dysplastic characteristics of EA causes extreme variations in clinical presentation from the neonate to the adult [7–9] (Figures 28.1–28.2, Table 28.1). The septal and posterior leaflets vary in the apical displacement of their attachments, and in approximately one third of cases the septal and/or posterior leaflets may remain adherent to the ventricular myocardium due to a failure of delamination. The anterior leaflet is attached at the functional annulus in a position superior to the other leaflets, but it is morphologically abnormal. Large with apparent redundant tissue, the leaflet frequently appears sail‐shaped, often with fenestrations, and with abnormal RV attachments at the boundary of the inlet and trabecular areas. The anterior leaflet and/or the shortened chordae/dysplastic papillary muscles can restrict blood flow from the atrium/atrialized RV to the trabecular RV. Slits or perforations in the abnormally fixed anterior leaflet can be a significant obstruction. The shortened chordae extend from dysplastic papillary muscles. The trabecular RV is small, and sometimes very small, lacking an inlet chamber. Trabecular RV myocardial function can be normal or impaired with thin walls. An interatrial shunt is almost invariably present as over one third will have an ASD and most of the remainder will have a PFO.

The line formed at the site of the distally displaced tricuspid leaflets serves as a functional TV ring and is the boundary between the trabecular and atrialized portions of the RV (Figure 28.3). Above this line of the distally displaced TV leaflets, the inlet portion of the anatomical RV serves as part of the RA. The atrialized portion of the RV is often thin and dilated with an abnormal ventricular electrical conduction pattern. Extreme thinning of the atrialized or inlet RV wall causes it to exhibit paradoxical movement with ventricular systole and dilation with RA contraction. The RA is dilated and sometimes massively dilated. The dilation of the atrialized RV creates an abnormal position for the interventricular septum, compromising left ventricular (LV) geometry and reducing the size of the LV chamber. There is increased fibrosis in both ventricles.

On prenatal ultrasound screening, the most severe forms of EA present with hydrops fetalis characterized by a massively enlarged heart and pulmonary hypoplasia. Lesser affected infants will have a neonatal course dependent on the severity of the EA defects, ranging from asymptomatic to cyanosis of varying degrees. Cyanotic neonates with severe obstruction will show signs of CHF that could lead to death. In general, cyanotic neonates with EA require intervention for survival. For lesser affected infants, the clinical presentation ranges from asymptomatic to progressive CHF depending on the degree of apical displacement of the TV. Diagnosis is sometimes delayed until symptoms present in older children or young adults, and less commonly in middle age or later. Generally, exercise tolerance is minimally impaired in the mildly affected unless the foramen ovale is not patent. Adults who present with CHF from long‐term effects of tricuspid regurgitation (TR) have a poor prognosis without definitive intervention. Severity cyanosis in children and young adults with EA is associated with a poor prognosis. Even milder forms of EA that present in late childhood, adolescence, or young adulthood often result in death from CHF in the second and third decades of life without surgical intervention. For those asymptomatic individuals who have not developed CHF, up to 20% may die of atrial and ventricular arrhythmias, sometimes as a sudden death. Paradoxical emboli, abscess formation, and less commonly endocarditis contribute to later fatalities [10].

Pathophysiology

The TR of EA and the degree of downward displacement of the TV variably impair adequate development of the heart. Diminished flow through the RV in utero may play a role in the development of right ventricular outflow tract obstruction (RVOTO), PS, and even PA. Significant TR places a volume load on the RV that results in a largely dilated RV that impairs LV function. Severe TR produces a massively ballooned RA. As pulmonary vascular resistance (PVR) decreases and stabilizes to near adult values, forward flow in the neonatal right heart can cause EA signs to improve [11, 12]. A cyanotic neonate with an unrestrictive ASD may eventually become acyanotic with acceptable cardiac output (CO). However, an infant with a restrictive ASD can have a low CO due to LV impairment from malposition of the interventricular septum with paradoxical motion.

The distortion of atrial and ventricular chambers with EA is associated with arrhythmias that can further impair function and be life‐threatening. As many as 25–30% of individuals will have atrial flutter, atrial fibrillation and paroxysmal supraventricular tachycardia. Other electrophysiological abnormalities are also frequently present [1] (Table 28.2).

Familial genetically inherited forms of EA are sometimes associated with LV noncompaction cardiomyopathy. In fact, the type of CHD most associated with this myopathy is EA. This combination is associated with mutations in the B‐myosin heavy chain gene MYH7. Although autosomal dominant, gene penetrance is variable as some individuals do not have cardiac abnormalities [13]. Characteristics of LV noncompaction include prominent trabeculations with deep intratrabecular recesses that give the LV a spongy appearance on cardiac ultrasonography. Added risks of CHF, arrhythmias, thromboemboli, and sudden cardiac death occur with this combination [14]. Recent genetic analyses of patients with EA suggest multiple genetic associations with genes involved with myocardial development or function other than MYH7 including NKX2‐5, TTN, MYH6 as well as a number of various single nucleotide alterations, genetic locus deletions/duplications and copy number variants [15] not infrequently associated with cardiomyopathies.

Progressive right heart failure resulting from TR, an inadequately sized RV pumping chamber, and other right‐sided obstruction combined with the EA TV are sometimes indications for surgery in the infant or child. Otherwise, moderate CHF can be treated with diuretic therapy, perhaps combined with digoxin. Medical therapy and perhaps catheter ablation can be used to control some types of arrhythmias. However, if deterioration of the TV and RV appears progressive, long‐term outcome will be improved with earlier surgical intervention [16].

Surgical and transcatheter approaches and outcomes

The timing of intervention for EA is determined by the degree of apical displacement of the functional TV, the competency of the TV, the presence of PA or circular shunting, and the age of the patient (Figure 28.4). Depending on the size of the trabecular RV, patients may undergo two ventricle repair or be palliated with one‐and‐one‐half (1.5) or single ventricle surgical pathways. Timing of intervention in neonates also takes into account potential RVOTO and allowance for PVR to resolve to near adult pressures. Only the most severely compromised infants are generally considered for cardiac transplantation [11] such as those with poor biventricular function and/or uncontrollable arrhythmias. Decision‐making for the type of surgical repair or palliation depends first on the age of the patient and secondly on two key elements: the TV morphology and the size of the trabeculated RV (Figure 28.5). A number of infants with adequate trabecular RVs have successfully undergone two ventricular repairs.

In 1958 after studying EA heart specimens, Hunter and Lillehei [17] suggested a potential repair for the TV but advances in valvuloplasty ultimately led to the first successful EA TV repair in 1963 [18]. From 1972 onward, further refinements in valvuloplasty by Danielson et al. [19] and others have improved survival for patients with EA (Table 28.3).

Techniques for valvuloplasty of the EA TV have evolved for nearly 60 years. A technique introduced in 1972 altered the anterior leaflet of the TV such that it would approximate the ventricular septum or the small, malformed septal leaflet during systole. Coaptation of the TV was facilitated by plicating the TV annulus at the apical boundary of the atrialized RV to reduce annulus diameter [19]. Further modifications for mobilizing and fixing the anterior and posterior leaflets at the true tricuspid annulus while utilizing a valve ring ensued [9]. Some infants with adequately sized RVs have done well with an aggressive two‐ventricle repair that included reconstruction of a monocuspid TV from the anterior leaflet with or without translocation of the leaflets to the true annulus, ventriculorrhaphy, reduction atrioplasty, subtotal closure of the ASD, and repair of other associated defects [20]. Others have focused on a bicuspid TV repair without repositioning the valve to the true annulus [21].

Building on a previous technique, da Silva et al. [22] developed a method known as the cone reconstruction that enhances available valve tissue by surgically delaminating leaflets attached to the RV wall and septum. The cone reconstruction of the TV for EA began to be developed in 1989 and has evolved to become a successful option for patients with adequate available valvar tissue and trabecular RV chambers. The TV leaflets are mobilized and reattached to the true TV annulus. The anterior and posterior leaflets are sutured together into a cone shape, incorporating the septal leaflet into the cone when possible. The atrialized RV is longitudinally plicated. Flexible annuloplasty rings (partial rings for children to allow for growth) are sometimes used to add stability to the dilated TV annulus [23] (Figure 28.6). Although cone reconstruction has been successful in neonates [24, 25] and small infants [26], valve rings are not an option for these small patients. When tissue is found to be insufficient, leaflets can be augmented with patch material [27, 28] (Figure 28.7). The cone operation improves coaptation of the TV leaflets and allows for centralized flow.

Utilization of a semi‐functional RV by combining RV output to the MPA from the inferior vena cava (IVC) with a bidirectional Glenn (BDG) anastomosis in a 1.5 ventricular repair can be beneficial. Compared to patients converted to single ventricle physiology, 1.5 ventricular pulsatile flow to the pulmonary arterial tree might reduce MAPCA development while inclusion of hepatic venous flow to the pulmonary arterial tree might reduce formation of pulmonary arteriovenous malformations. Even a hypoplastic RV may increase CO with increased cardiac demand beyond what could occur with a Fontan circulation. The BDG can be used to reduce RV preload to hypoplastic EA RVs or those with moderate degrees of TV stenosis, allowing for closure of a coexisting ASD or PFO.

In some cases of severe EA, there may be no identifiable TV leaflet tissue available for reconstruction. In the absence of available leaflet tissue combined with a severely dilated dysfunctional RV and secondary LV compression, a fenestrated RV exclusion procedure with a systemic‐to‐pulmonary arterial shunt may be the best option for an infant [30]. The modified Starnes procedure is accomplished by placing a patch with a 5 mm fenestration at the level of the true tricuspid annulus while allowing the coronary sinus to remain on the RA side of the patch. The fenestration allows for thebesian venous drainage from the excluded RV to the RA. If there is pulmonary arterial insufficiency, the RV to pulmonary connection is interrupted. As with all single ventricle palliations, an unrestricted atrial communication is ensured. Later, the infant or child may advance to a BDG or Fontan palliation. A limited follow‐up for 12 patients has shown that the RV involutes sufficiently to allow improved geometry and function of the single LV [31]. The Sano RV exclusion technique [32] for EA is similar but employs an RV to pulmonary artery conduit rather than a systemic‐to‐pulmonary shunt to provide PBF. The advantage of the modified Starnes procedure over the Sano RV exclusion technique is that the already reduced functional RV myocardium is less compromised without the ventriculotomy required for the RV to pulmonary artery conduit.

Complications of the cone procedure are similar to other TV repairs for EA. Inadvertent tricuspid stenosis or suture dehiscence are possible. Sutures too near the AV node can cause third‐degree heart block. Distortion caused by plication of the atrialized RV and TV annulus can impair right coronary artery blood flow. Outcomes are compromised when neonatal EA is associated with RVOTO, PA, small pulmonary arteries, or any congenital disease that causes LV dysfunction.

Rhythm disturbances can occur at any time with EA. Temporary pacing wires should be placed on the RA and RV near the conclusion of surgery as postoperative pacing could be necessary. Generally, teenaged and adult patients who do not require postoperative pacemakers have fewer rhythm disturbances on follow up [33]. Wolff‐Parkinson‐white accessory pathways, often near the orifice of the TV, are present in 10–20% of EA.

Outcome studies are limited for the cone reconstruction. A follow‐up of 52 patients ranging in age from 0.25 to 49 years (mean 18.5 ± 13.8 years) showed that the cone repair maintained its integrity and there was an increase in RV function relative to body surface area indexing. Two of the 52 died postoperatively in‐hospital and one was lost to follow up resulting in a statistical survival of 86.2 ± 8%f at 7 years. Of the followed 49, four underwent TV revision (3, 4, 5, and 10 years postoperatively), one received a pacemaker for intermittent episodes of complete AV block 1 year after surgery, three had atrial arrhythmias (one successfully ablated and the other two medically controlled). Eleven had Wolff‐Parkinson‐White syndrome and had the anomalous bundle surgically sectioned; ten were successful and one had repeated ablations, developed TR, and then underwent TV revision 5 years postoperatively [34].

A single institution review of 151 EA patients with a mean age of 28 years (56 patients less than 18 years of age) who underwent either cone reconstruction (n = 38, age 31 ± 19 years), conventional repairs (n = 94, age 26 ± 18 years), or TV replacement (n = 19, age 36 ± 21 years) presented mid‐term follow up comparisons for cone repair, conventional repairs, and TV replacement. Cardiopulmonary bypass (CPB) times as well as aortic cross clamp times were longer for cone repairs than either conventional repairs or TV replacement. Cone repair was more successful than conventional repairs at mid‐term follow up (8 years) with moderate or less TR (p = 0.031) and a reduced incidence of post‐repair severe TR that did not reach clinical significance. Of note, most of the cone repairs were performed more recently than many of the conventional repairs [35].

In the largest series to date from the Mayo Clinic [28], 235 consecutive cone repairs for patients with EA and a median age of 15 years (range 6 months to 73 years) showed only one early death of a 50‐year‐old from low CO syndrome related to endocarditis from pacemaker leads. Extracorporeal membrane oxygenation (ECMO) was needed for the one adult early mortality patient and for 5 pediatric patients with severe preoperative RV dysfunction and dilation. Cone repair was the primary correction in 80% and a re‐repair in 12%. Early reoperation for recurrent TR occurred in 5.9% (7 children and 7 adults). TV replacement was ultimately required for 6/7 adults, but 6/7 children had a successful reoperation. Of those requiring reoperation, 11 of the 14 were in the first third of the series, suggesting a learning curve for a successful cone repair. Supplemental techniques were used in many, including the BDG anastomosis in approximately 20% (41 children and 5 adults), annuloplasty bands, leaflet augmentation, and use of neochordae.

In general, TV replacement is reserved for irreparable TV and RV anatomy as reoperation and repeat cardiotomy for TV replacements will likely be necessary for the patient’s lifetime. In addition, options for prosthetic valves are limited or non‐available for small infants and children. Some teenaged or adult patients with late diagnoses might have incurred TV leaflet damage from turbulent blood flow or endocarditis that preclude successful repair, and TV replacement may be the best option. For select patients such as the elderly, TV replacement might be considered if advantages of lessened CPB time outweigh the longer time needed for TV repair. Bioprosthetic valves are preferable in the tricuspid position due to their lower thrombogenicity over mechanical valves. When placing the prosthetic TV, care is exercised in avoiding the conduction system on the septal side and the right coronary artery on the anterior and inferior sides of the implanted TV as well as avoiding the right ventricular outflow tract (RVOT) and impingement of the valve struts on the AV node. Similar considerations will apply to future development of percutaneous TV replacement.

Older children and adults with preoperative paroxysmal atrial fibrillation or atrial flutter might be candidates for a modified right‐sided maze procedure or cavotricuspid isthmus ablation using either radiofrequency or cryoablation [23] (Figure 28.8). Those with continuous atrial fibrillation may do better with a biatrial maze [36].

Anesthetic considerations

Preoperative

For neonatal presentation of EA, signs of right heart failure and systemic hypoxemia are most critical. Dyspnea, cyanosis, and hepatomegaly suggest that the infant should be supported such that demands on CO and oxygen consumption are minimized. The most severely affected infants benefit from intubation, mechanical ventilation, paralysis, and sedation to reduce work of breathing and demands on CO. Oxygen, inhaled nitric oxide (iNO, if pulmonary hypertension is suspected), inotropic support, and possibly PGE₁ may increase oxygen delivery. For the less affected infant, signs of fatigue with feeding, feeding intolerance, irritability, diaphoresis, dyspnea, and episodic cyanosis with distress suggest a poorly functioning heart. Oxygen, milrinone, and possible PGE₁ may be beneficial prior to anesthesia. Some neonates will manifest a gradual improvement in right heart forward flow and a reduction in right‐to‐left shunting and cyanosis as TR declines. Neonatal surgical intervention, when possible, is delayed until PVR has declined significantly.

For the toddler, older child, adolescent, or even young adult, functional symptoms of dyspnea with exertion, excessive fatigue with daily activities or as compared to peers, and certainly signs of cyanosis as well as the trends in symptomatology in recent months give some insight into the severity of EA. In the older child and young adult, syncope, chest pain, and palpitations should be investigated for the presence of arrhythmias.

Physical examination often reveals a soft, high‐pitched systolic murmur, sometimes accompanied by triple or even quadruple heart sounds. A mid‐diastolic murmur is sometimes found at the left sternal border and apical areas and has a soft, scratchy sound. A persistently split‐second heart sound due to delayed emptying of the RV is usually present and varies little with respiration. Pediatric patients with myocardial failure are diaphoretic, tachypneic, and irritable. Chest auscultation can be notable for rales if LV function is impaired by a dilated RV. Abdominal examination often reveals hepatomegaly on palpation. Moderate to severe cardiomegaly is found on the chest radiograph, and pulmonary vascularity is reduced. The silhouette of the heart is globular due to the enlarged RA. In fact, the electrocardiogram (ECG) usually shows an increased duration for the P‐wave suggesting right atrial enlargement, an increased PR interval, and not unusually a complete or incomplete right bundle branch block. In at least 10–15% of patients, the pre‐excitation patterns of Wolff‐Parkinson‐White syndrome are present. An echocardiogram is usually diagnostic for EA, showing a large TV orifice with apical displacement of the septal leaflet [29] (Figure 28.9). Cardiac catheterization is seldom useful, even for the most commonly associated defects, and place the patient at risk for development of tachyarrhythmias. Magnetic resonance imaging (MRI) can be valuable in estimation of the size of the functional RV and accurately measuring the displacement of the TV leaflets (Figure 28.10). Though both MRI and echocardiography are useful in detecting associated defects, echocardiography may underestimate the degree of TR but is more effective in detecting small shunts from associated defects than MRI [37].

Hypoxemic neonates should be managed with interventions aimed to decrease and avoid increasing PVR. For the mechanically ventilated neonate, adequate tidal volumes and minute ventilation must be achieved with minimum airway pressures. Those infants with marginal heart function may benefit from iNO by reducing PVR and enhancing right heart to pulmonary artery flow. In addition, functional and anatomical obstructive components to PBF may be further defined by the addition of iNO as poor right heart function is anticipated to improve with iNO while anatomical obstructions in the RVOT, PV, and PAs will remain. In the first couple weeks after birth, pulmonary arterial blood flow may require augmentation with a PDA maintained with PGE₁. However, too much flow through a large PDA can result in cardiac failure and loss of systemic and pulmonary perfusion with a phenomenon known as “circular shunt” [38] (Figure 28.11). Circular shunt results when generous flow to the pulmonary arterial system from the aorta via the PDA follows a retrograde path of least resistance when the PV and TV are incompetent and there is an interatrial communication. Sequentially, flow proceeds from the PDA, BPA, MPA, PV, RV, RA, ASD or PFO, LA, LV, and finally the aorta. Perfusion of the pulmonary capillary bed is diminished and CO to the vital organs is reduced. PGE₁ should be discontinued so that the PDA becomes smaller and more resistant to flow, reducing the circular shunt and high output failure [12].

Most neonates and young infants may not require anxiolytic premedication. Older infants, those who have developed stranger anxiety (approximately 9 months of age), and children often benefit from anxiolytic administration of midazolam. Midazolam may be given orally (0.5–0.75 mg/kg up to 15–20 mg) or intravenously (IV) (0.1–0.15 mg/kg up to 2–4 mg). Anxiolysis can be helpful in reducing or avoiding decreases in PBF that can result with crying or breath‐holding during application of the mask anesthetic. In some cases, a sleeping child who has received dexmedetomidine can be safely transported and undergo a safe anesthetic induction, but this technique requires planning. Loading with 0.5 to 1.0 μg/kg IV over 10 minutes is often sufficient but requires monitored attention for potential bradycardia. For patients who do not yet have IV access and are to undergo a mask anesthetic induction or merely have a non‐stimulating procedure (such as a sedated transthoracic echocardiogram), intranasal dexmedetomidine is administered with a nasal atomizer (2–3 μg/kg, 100 μg/mL) often results in adequate sedation. The time required for mean onset of sufficient sedation is 10–24 minutes for 3 μg/kg [39]. Reducing ambient light and background noise while ensuring that the child is warm and comfortable facilitates the sedative effect. Relative contraindications for dexmedetomidine include poor CO, hypovolemia, bradycardia or risk for bradycardia, AV nodal block, or medications that delay AV conduction or increase vagal tone [40].

Incidence, anatomy, and natural history

TOF is the most common cyanotic congenital heart disease with an estimated incidence of 1 in 2,500–3,000 live births [2]. Although reports of this abnormality can be dated back to 1671, it was Etienne Fallot in 1888 who reported the four cardinal distinguishing features and proposed clinicopathophysiologic correlations derived from extensive clinical and postmortem studies. This “blue malady or cardiac cyanosis” as Fallot referred it, was named “tetralogy of Fallot” in 1924 by Maude Abbott [42].

The first surgical treatment for TOF occurred in 1945, when the first Blalock‐Taussig shunt (BTS) was performed. The tetrad of TOF consists of (Figure 28.12):

1. RVOT obstruction
   
2. A large unrestrictive VSD
   
3. Overriding aorta
   
4. RV hypertrophy

One embryologic theory states that TOF results from uneven conotruncal spiral septation leading to a smaller MPA and a larger aorta. Another theory, van Praagh’s, suggests that the TOF stems from one abnormality – the underdevelopment of the subpulmonary infundibulum (infundibulum means “funnel” in latin). The hypoplastic infundibulum, in turn, affects the surrounding structures as follows: (i) the conoseptum is deviated anterior and leftward contributing to obstruction to flow, (ii) the aorta is shifted rightward over the ventricular septum facing the VSD and facilitates flow of the ejected RV blood into the systemic circulation, (iii) a VSD results from the malaligned conoseptal tissue failing to join the remainder of the ventricular septum, and (iv) postnatal RV muscle hypertrophy develops from cumulative work against the higher pressure load imposed by a stenotic outflow tract and systemic pressure transmitted across the VSD. The phenotype of TOF with PS varies from patient to patient. Although no two TOF cardiac anatomies are the same, physiologically they follow similar guiding precepts for management. Of note, the normal RV of a newborn infant has similar thickness to the LV because of exposure to systemic pressures. As normal cardiac development progresses, the RV becomes thinner relative to the LV as a result of their markedly different afterloads.

In TOF, the RVOTO often occurs at several levels and has fixed and dynamic components. The fixed obstructions occur at the valvar and supravalvar levels. At the valvar level, the pulmonary annulus is frequently hypoplastic with a bicuspid valve that contains dysplastic leaflets. At the supravalvar level, hypoplasia of the MPA can be localized at the sinotubular ridge or be diffuse and extend into the BPAs. The RVOTO dynamic component comes from the hypertrophied subvalvar muscle bundles. The hypertrophy develops over time in response to the increased pressure load. This dynamic component is thought to play a major role during hypercyanotic episodes associated with TOF. The VSD is usually large and unrestrictive. The bundle of His courses at the posteroinferior edge of the defect, near the anteroseptal leaflet of the tricuspid valve, and can be inadvertently injured during VSD closure [43, 44] (Figures 28.12–28.14).

Other cardiac anomalies associated with TOF are found in about 40% of patients, and they have implications for the optimal surgical repair strategy [44–56] (Table 28.4). Also, anatomical variations influence surgical conduct, e.g. degree of aortic override and location of conoseptum determine the patch size to close the VSD and baffle the LV flow to the aorta [57].

Unique TOF variants include TOF with PA/VSD/MAPCAS (7%) and TOF with absent PV (5%) [58, 59]:

• In TOF with PA/VSD/MAPCAS, total lack of blood throughput leads to severe underdevelopment of the MPA and peripheral pulmonary artery branches such that the MPA may be completely absent, and the BPAs are hypoplastic, non‐confluent or even non‐existent. MAPCAs often develop to supply blood flow to the lungs. The lungs often show aberrant arborization, unless that side is supplied by a PDA. Some lung lobes have blood supply via BPAs, MAPCAs or both. The surgical approach to this variant varies significantly from that of classic TOF and is described later in this chapter.
  
• In TOF with absent PV, the PV is ring‐like with valve cusp remnants which lead to both stenosis and free pulmonary insufficiency (PI). The MPA, BPAs, and distant peripheral pulmonary arteries are massively dilated, causing compression of the associated airway. The ductus is often absent. Significant tracheobronchial malacia, often with compression, is characteristic of this condition. In severe cases, the newborn presents in respiratory distress and often requires endotracheal intubation with high levels of positive end‐expiratory pressure (PEEP) to improve airway patency and decrease air trapping. Prone positioning can also be useful in respiratory management. During surgical repair, the TEE probe has been known to compress the large airways and worsen obstruction. Postoperatively, many patients require long‐term ventilatory management due to persistent tracheobronchomalacia and lung disease.

Typically, TOF presents as an isolated lesion, although in 15–30% of patients TOF can present with other abnormalities or as part of a syndrome [60–62]. The most common include the 22q11 microdeletion‐associated syndromes called DiGeorge, velocardiofacial syndrome, and conotruncal anomaly face syndrome. Other conditions include trisomy 21 and VACTERL association, among others [60–71] (Table 28.5). There is a mild association of familial inheritance of TOF. Other genetic bases for TOF have been linked to mutations on NKX2‐5, JAG1, chromosome 20p12, chromosome 5q35, the GATA4 gene on chromosome 8p23, ZFPM2, TBX1, and GATA6 [72].

The natural course of uncorrected TOF reveals about 50% mortality in the first 5–10 years of life. Prolonged survival is enabled by the persistence of pulmonary flow via the PDA and /or collaterals, and by compensatory hypoxic mechanisms such as erythrocythemia. Uncorrected, it is rare for survival beyond the 4^th decade of life. The morbidity and mortality are secondary to chronic hypoxemic ramifications such as thromboembolism, brain abscesses and endocarditis [73].

Modern operative mortality is low with an overall rate of less than 2% in developed countries [74], and less than 4% in low‐to‐middle income countries [75]. A report analyzing the only collaborative database of congenital heart surgery in low‐to‐middle income countries found that over half of the children undergoing primary TOF repair were over 1 year of age. Interestingly, age at primary repair was not a risk factor for mortality. Poor nutritional status and hypoxemia were associated with increased infection rates and mortality [75]. Athanasiadis et al. found that syndromic patients with TOF had an all‐cause mortality rate of 9.8% [62]. Long‐term survival 40 years after TOF repair has been quoted to be over 70% with late mortality from ventricular fibrillation and heart failure [76].

Pathophysiology

Patients with TOF manifest a wide spectrum of clinical presentations depending on the severity of RVOTO and degree of right‐to‐left shunting of venous blood into the systemic circulation. The unrestrictive VSD allows a near equalization of RV and LV pressures. Shunting direction will be determined by the balance of systemic vascular resistance (SVR) and RVOTO. Most patients are initially asymptomatic and acyanotic – the “pink tets.” Some of them have near‐normal sized pulmonary valvar and supravalvar areas with minimal RVOTO. As PVR drops, the increasing left‐to‐right shunting through the unrestrictive VSD leads to pulmonary overcirculation and even CHF. Cyanosis eventually presents at about 6–12 months when infundibular muscles become hypertrophied and RVOTO increases over time. In contrast, some babies present with severe cyanosis shortly after birth and need immediate medical management for stabilization of PBF while preparing for surgical intervention. In these patients, the main obstruction is usually at the level of the PV.

A number of patients develop acute hypercyanotic events or “tet spells,” a sudden and profound hypoxemic event that can result in loss of consciousness, stroke, or death. Typically, hypercyanotic episodes occur in association to periods of increased sympathetic activity such as crying, pain and fright. Other predisposing conditions include dehydration, acidosis, and fever – events which decrease SVR and promote right‐to‐left shunting with resulting arterial desaturation. Additionally, it is postulated that infundibular muscle spasms with acute worsening of RVOTO lead to right‐to‐left shunting and drastic PBF reduction. The resulting acidosis and hypoxemia decrease SVR, furthering the right‐to‐left shunting. Prompt aggressive treatment to halt the vicious cycle, reverse the shunt, and restore pulmonary flow is imperative. Treatment for hypercyanotic episodes is described later in the chapter. During these events, awake patients often hyperventilate, likely to mitigate the hypoxia and acidosis. Squatting behavior during the spell is also observed in older children. Squatting increases SVR from compression of the iliac arteries, increasing RV preload with enhanced venous return generated by elevating intraabdominal pressure and compressing veins in the leg musculature. The result of squatting is reduced right‐to‐left intracardiac shunting and increased PBF.

Progression of infundibular and RV hypertrophy from exposure to high pressure loads results in anatomical changes that complicate the perioperative course and contribute to postoperative RV dysfunction: (i) the RV becomes less compliant with abnormal diastolic relaxation, requiring high filling pressures for adequate CO, (ii) the hypertrophied RV and muscle bands increase surgical complexity, (iii) the increased RV muscle mass may reduce the myocardial protection of cardioplegia, a reduction in protection that in some instances is compounded by abnormal coronary artery distributions, and (iv) muscle resection or division is often required to relieve the RVOTO.

Presently, complete surgical correction is commonly performed in early infancy for most patients. Early repair is thought to prevent the development of RV hypertrophy, minimize the effects of cyanosis and polycythemia, allow improved pulmonary vascular development via greater PBF, and avoid the occurrence of hypercyanotic episodes.

Fetal ultrasonography can diagnose TOF prenatally. After birth, most neonates with TOF are acyanotic and present with non‐specific physical examination findings. Auscultation shows a crescendo–decrescendo systolic murmur best heard at the left upper sternal border prompting further investigation. Clubbing is not a feature at this stage; it only becomes apparent after prolonged periods of chronic hypoxemia. Ductal closure will uncover cyanosis in those with severe PS and ductal‐dependent PBF. The ECG reveals persistent RV hypertrophy and right axis deviation beyond the neonatal period. The chest radiograph shows a “boot‐shaped” cardiac silhouette, resulting from the RV hypertrophy displacing the apex upwards and the hypoplastic MPA creating a concave upper left heart border. Transthoracic echocardiography is effective at establishing the TOF diagnosis and demonstrating related important features: (i) extent and anatomical characteristics of RVOTO, (ii) VSD size, number and locations, (iii) coronary artery distribution, (iv) additional cardiac abnormalities including ASD and aortic arch‐sidedness, and (v) biventricular function.

Most children are diagnosed during infancy in countries with routine access to modern medicine. In regions of the world with limited access to care, it is common to see children with uncorrected TOF present at much older ages with advanced pathology.

Surgical and transcatheter approaches and outcomes

Surgical and transcatheter palliation

Palliation, meaning “lessening the intensity of disease,” comes from the late Latin word “palliatus,” meaning to cloak or to mask. A palliative intervention does not offer correction but rather a relief for a condition, generally only temporary. For TOF, the first operative procedure was palliative, the classic BTS by Blalock in 1945, an end‐to‐side anastomosis of the subclavian artery to the right pulmonary artery branch, to provide a source of pulmonary flow. The anastomosis is usually performed on the side ipsilateral to the innominate artery. Direct anastomotic aorto‐pulmonary shunts, such as the now nearly obsolete Potts and Waterston shunts, are difficult to take down due to their anatomical locations. The mBTS is the most commonly used systemic‐to‐pulmonary shunt (Figure 28.16). It consists of prosthetic graft placed between the innominate artery or the subclavian artery and the ipsilateral BPA. When anatomy is unfavorable for a mBTS, a central shunt, comprising a graft placed between the ascending aorta and the MPA, may be placed. In TOF, the shunt augments PBF until complete primary repair can be achieved. The mBTS allows early palliation without sacrificing the subclavian artery. Resistance from the graft diameter (usually 3.5–4 mm) and length regulates PBF. The locations of the mBTS and central shunts allow exposure and maneuverability during subsequent repairs. A right‐sided mBTS is most common due to more favorable surgical exposure during take down and less risk of phrenic nerve injury compared to a left‐sided mBTS. Although mBTS was traditionally done via a thoracotomy, many centers are performing mBTS via median sternotomy. This approach also facilitates patch augmentation of narrowed BPAs with bypass support. A downside of a mBTS is that the shunt can frequently lead to stenosis and distortion of the BPA [44].

Patients who are unsuitable candidates for surgical palliative shunts, often small and critically ill neonates or infants, can undergo the less invasive transcatheter palliative interventions such as pulmonary balloon valvuloplasty and stent placement in the RVOT or PDA to maintain PBF. Candidates for ductal stenting have an anatomically suitable ductus as well as an additional source of PBF. Pulmonary balloon valvuloplasty alone seldom produces long‐lasting improvement, as the dilated RVOT often returns to its original stenotic state. Cutting balloons or primary stent implants are associated with longer‐lasting improvement in relief of obstruction. Application of stents should be done in consultation with the cardiac surgeons as the stents impact the operative conduct of the full repair [52, 83, 84]. See Chapters 19 and 34 for further discussion of RVOT and PDA stenting.

Surgical repair

Preoperative knowledge of pertinent anatomic TOF details is important for surgical planning and successful repair, including size and nature of RVOTO at the subvalvular, valvular, and supravalvular levels, coronary artery distribution, type and number of VSDs, and any other associated cardiac anomalies.

The first successful full repair of TOF was performed on a 10‐year‐old boy by Walton Lillehei in 1954. In the early era of TOF repair, the goals of surgery were relief of RVOTO and VSD closure via ventriculotomy while preserving RV function. In the 1960s, full repair was reserved for children 4–6 years of age because surgical mortality was too high for younger patients. Later, use of deep hypothermic circulatory arrest improved survival and opened the door for full primary repair during infancy.

Early repair has hemodynamic and anatomic advantages for the developing heart. Although some centers offer neonatal elective full repair, most centers prefer to perform elective full primary repair between 3 and 6 months of age and prior to 12 months for those with a palliative shunt. The increased duration of longitudinal postoperative follow‐up reveals that adults with repaired TOF exhibit medical and surgical sequelae such as impaired exercise capacity, atrial and ventricular arrhythmias, RV and LV dysfunction, cardiac failure, and sudden death. The pathophysiology of these late complications appears related to the effect of extensive ventriculotomy, coronary artery compromise and PV destruction. Findings from outcomes have led to changes in the surgical approach by emphasizing the preservation of the RVOT apparatus, sparing PV injury, minimizing ventriculotomy incisions, and reducing residual VSDs. Hence, transatrial and transpulmonary approaches with valve‐sparing techniques are emphasized with only selective use of transannular patches (Figure 28.17). The surgical approach is via median sternotomy with CPB‐assist. The thymus size is noted prior to subtotal excision due to association to 22q11.2 microdeletion syndromes with TOF.

Upon cardiac exposure, the coronary artery distribution is assessed. After CPB commencement and cardioplegia, the RVOT is examined through a right atriotomy via the TV, and the PV annulus is sized with calibrated dilators. Muscle bundles are divided as needed. A PV commissurotomy can be performed transatrially if exposure is adequate; otherwise, it can be accessed via a transpulmonary approach by a longitudinal incision in the MPA. If preservation of the PV is not feasible, a right ventriculotomy with placement of transannular patch will be done to augment the RVOT size. The VSD is closed using a patch, avoiding the AV node or bundle of His that passes adjacent to the VSD margin. The atrial level shunt is closed if present. If postoperative RV dysfunction is expected, a small atrial communication (“pop‐off”) is left to allow LV filling and preload with a degree of right‐to‐left shunting. Patch augmentation of BPA stenosis is performed as needed. In some patients, a RV‐to‐pulmonary artery conduit may be necessary to avoid injuring a coronary artery crossing the RVOT (Figure 28.18). TEE is used after separation of CPB to assess for adequacy of repair, residual shunts and defects, and ventricular function. An RV:LV pressure ratio greater than 0.7 usually indicates inadequate relief of RVOT obstruction, with the caveat that early post‐CPB pressure measurements do not always correlate to later measurements and might prompt unnecessary revisions. If residual shunts are suspected, a comparison of PaO₂ from simultaneous blood gas measurements taken from the superior vena cava and the MPA can be helpful. Temporary atrial and ventricular pacing wires are placed prophylactically for the management of postoperative arrhythmias such as heart block and junctional ectopic tachycardia (JET) following TOF repair.

Long‐term surgical complications

Most patients with repaired TOF will live to adulthood; however, many will require reintervention before 30 years of age to address residual disease. The most common sequela is PI. Other sequelae include BPA stenosis, residual VSDs, and RVOT aneurysmal dilation. Chronic PI leads to RV volume overload, RV dilation and dysfunction, and ventricular arrhythmias. Eventually, these sequalae affect the LV and cause biventricular dysfunction and heart failure. Monitoring for symptomatology and progression of RV dilation is essential. An increasingly used monitoring modality is cardiac MRI for the longitudinal evaluation of volumetric ventricular measurement, PI fraction quantification, and RV functional status [85]. Ideally, a PV replacement is performed prior to irreversible RV dysfunction from the effects of PI but as late as possible to allow placement of an adult‐sized valve to decrease the number of re‐interventions needed in a patient’s lifetime. Bioprosthetic valves deteriorate over time, and most patients will require another replacement within a decade. For symptomatic patients, PV replacement is indicated. For asymptomatic patients, the timing and indications for PV replacement is unclear. Professional organizations have published criteria to guide these decisions [86].

Transcatheter pulmonary valve implantation

Multiple PV interventions are needed over the lifetime of the TOF patient. The most common late re‐intervention in the patient with repaired TOF is PV replacement. Nonsurgical options for PV replacement are currently available as transcatheter valve implants for patients with dysfunctional RV‐to‐pulmonary artery conduits, such as the Medtronic Melody valve (Medtronic, Inc., Minneapolis, MN), a stent‐mounted bovine jugular valve and the Edwards SAPIEN XT valve (Edwards Lifesciences Corporation, Irvine, CA), a stent‐mounted bovine pericardial valve. Pre‐stenting a RV‐to‐pulmonary artery conduit to prepare a landing zone for the PV to anchor is often necessary (Figure 28.19). Transcutaneous valves for the native RVOT without a circumferential conduit are under development. Knowledge of coronary artery location is necessary to avoid coronary artery compression during and after valve implantation. Other than coronary artery compression, complications include stent fracture, RV‐to‐pulmonary artery conduit tear, device dislodgement and infective endocarditis. This field continues to grow, and more transcutaneous device options will become available [87]. See Chapter 34 for additional discussion of transcatheter PV implantation.