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Ann Thorac Surg 2006;81:968-975
© 2006 The Society of Thoracic Surgeons
a Dipartimento Medico-Chirurgico di Cardiochirurgia e Cardiologia Pediatrica, DMCCP, Ospedale Pediatrico Bambino Gesù, Rome
b Dipartimento Cardiologia Pediatrica e Cardiochirurgia, University of Bologna, Bologna, Italy
Accepted for publication September 15, 2005.
* Address correspondence to Dr Michielon, Ospedale Pediatrico Bambino Gesù, P.zza S.Onofrio 4 00165 Roma, Italy (Email: guido.michielon{at}tin.it).
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Abstract |
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METHODS: This retrospective study reviews the outcome of 306 consecutive patients (median age, 5.1 months) who underwent primary (266) or staged (40) repair of TOF between 1994 and 2004. Total follow-up was 1,188 patient-years (mean, 57 months).
RESULTS: Genetic syndromes were documented in 85 patients (27.8%), including 22q11 deletion (27), trisomy 21 (13), vertebral, anal, cardiac, tracheoesophageal, renal, and limb abnormalities (VACTERL, 12), and others (33). Hypoplastic pulmonary arteries (PA) were more common in syndromic (19/85 = 22.3%) than nonsyndromic TOF (20/221 = 9.04%) (p < 0.001). Primary repair was performed in 82.4% syndromic and 88.7% nonsyndromic TOF (p = not significant [NS]). Ten-year actuarial survival was 94.1 ± 2.3% in nonsyndromic and 84.3 ±4.2% in syndromic TOF (p < 0.001). Ten-year survival was 96.3 ± 3.6% for del22q11, 100% for trisomy 21, 63.6 ± 14.5% for VACTERL, and 78.5 ± 7.3% for patients with other syndromes (p = 0.022). Survival in syndromic TOF with normal PA anatomy was 89.6 ± 4.2% for primary repair and 85.7 ± 12.8% for staged repair (p = NS); freedom from reoperation after complete repair was 74.4 ± 6.4% for primary correction and 56.3 ± 11.9% for staged repair (p = 0.04). Cox proportional hazard identified the presence of genetic syndrome (p = 0.011) and central PA hypoplasia (p = 0.002) as independent predictors of mortality.
CONCLUSIONS: Pulmonary arborization defects and genetic syndromes other than del22q11 or trisomy 21, are associated with worse outcome after correction of TOF. Primary TOF repair in syndromic patients with normal PA anatomy is a valid surgical strategy, with no additional risk for mortality and higher freedom from reintervention.
Tetralogy of Fallot (TOF) is the most common conotruncal cardiac defect, occurring in 1 in 3,000 live births. After the pioneering experience of Castaneda and colleagues [1], primary repair of this lesion is currently recommended in early infancy to minimize right ventricular (RV) hypertrophy and to promote alveologenesis. Tetralogy of Fallot and its variants have been observed as components in a number of genetic syndromes. Previous studies suggested that approximately 10% to 15% of TOF patients carry a 22q11 deletion (del22q11) [2, 3] and that 7% of TOF have trisomy 21 [4]. Teralogy of Fallot patients with Alagille syndrome carry a mutation in JAG1 (jagged1 gene) [5, 6] and VACTERL, CHARGE, or other syndromes can be associated with TOF [7, 8]. Patients with TOF and an associated genetic defect present a challenge to the cardiac surgeon and may face additional risk for primary repair; for example, if there is the need of extracardiac surgery for associated anomalies or because of immunodeficiency or altered compliance of the pulmonary vasculature. This study was designed to document the impact of proven or likely genetic defect on the current surgical outcome of TOF without pulmonary atresia.
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Material and Methods |
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Preoperative two-dimensional (2D) and Doppler echocardiography was performed in all patients. Further preoperative evaluation by cardiac catheterization was performed in 48 patients, when pulmonary arborization abnormalities such as discontinuous or hypoplastic PA branches, presence of multiple VSDs, or anomalous coronary artery patterns, were suspected at 2D echocardiography. Pulmonary artery hypoplasia was defined by a Nakata index less than 150 mm2/m2.
Operative Technique
Complete repair was accomplished under hypothermic cardiopulmonary by-pass (25°C to 28°C). A systemic-to-pulmonary shunt, if present, was divided. Ventricular septation was accomplished through a transatrial approach. A gluteraldehyde-treated autologous or bovine pericardial patch was anchored to the VSD margins utilizing pledget-reinforced interrupted mattress sutures. Relief of right ventricular outflow tract (RVOT) obstruction was achieved by division of the parietal band and paraseptal muscle bands, through a combined transatrial-transpulmonary approach. The RVOT reconstruction was accomplished after calibration of the pulmonary annulus and PA branches. Preservation of the pulmonary annulus by complete transatrial repair or limited infundibular patch plasty was accomplished when the Z score for pulmonary annulus diameter was at least –2. Transannular patching was used when the pulmonary annulus Z score was less than -2. Conduit interposition between the RV and the pulmonary confluence was rarely performed, usually to overcome major anomalous coronary patterns. Associated anomalies were corrected simultaneously, with the exception of a patent foramen ovale (PFO), which was left open in younger patients to allow for RV decompression. Right ventricular pressure and PA saturation were measured after discontinuation of cardiopulmonary bypass, to detect residual outflow obstruction and left-to-right shunting. Intraoperative transesophageal echocardiography was performed when residual lesions were suspected after repair.
Follow-Up
All survivng patients were followed in the pediatric cardiology outpatient clinic. Clinical examination, 12-lead electrocardiogram and 2D-echocardiography were performed at regular intervals to estimate tricuspid valve and RV function-pressure and to detect residual lesions or PA branch stenosis. Hemodynamically significant residual lesions were confirmed at cardiac catheterization prior to surgical or interventional procedures. Mean follow-up was 57 ± 23 months (range, 29 to 126 months) and was 99% complete and updated.
Statistical Analysis
Statistical analysis was conducted with the SAS Statview 1998 statistical software (SAS Institute Inc, Cary, NC). The 
2 analysis was used to compare discrete variables between syndromic and nonsyndromic TOF patients, while continuous variables, expressed as mean ± SD, were compared by unpaired t testing. Categorical analysis was conducted by 2 and Fisher exact tests. Freedom from time-related events was conducted according to actuarial and/or Kaplan-Meier technique; the resulting curves with 95% confidence limits were compared with log-rank testing and nomograms of the hazard function were obtained. Selected and separate end points were defined as death, reoperation, or interventional procedure. Early mortality was defined as death within 30 days from surgery or prior to hospital discharge. Variables associated with an increased risk of death and reinterventions were assessed by univariate logistic regression and by Cox proportional risk multivariate analysis.
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Results |
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Cardiac Repair
Primary TOF repair was accomplished in 266 patients (86.9%), while staged repair was performed in 40 patients (13.7%). Mean age at palliation was 3.6 ± 2.7 months, while mean age at primary repair was 6.4 ± 5.3 months (p = 0.22), suggesting that age per se was not the main criterion for surgical staging. Complete primary neonatal repair was accomplished in 8 patients. Staged repair was more common in syndromic (15/85 = 17.7%) compared with nonsyndromic TOF (25/221 = 11.4%), although this difference was not statistically significant (p = 0.18). The indication for palliation in the overall cohort included dyscontinuous PAs in 2, hypoplastic PAs in 23, and anomalous coronary artery pattern in 4 patients. Primary repair, moreover, was not favored because of functioning cervical esophagostomy and/or gastrostomy in 5 infants and because of neonatal age in 6. Presence of a genetic defect per se did not represent an indication for surgical palliation. Pulmonary blood flow was augmented with a modified Blalock-Taussig (BT) shunt in 34 patients, a central shunt in 4 patients, and balloon dilation of the pulmonary valve in 1 patient prior to TOF repair. Conduit interposition between the RV and the pulmonary bifurcation without VSD closure was performed in one patient with Alagille syndrome to promote the growth of diminutive PAs. Normothermic cardiopulmonary bypass was used during initial palliation in 8 patients. Early shunt failure occurred in 6 patients, leading to shunt revision in 5 and complete repair in 1. A modified BT shunt was downsized in one patient to control heart failure. Complete staged repair was achieved in 33/40 patients (82.5%), 7.2 ± 2.1 months after palliation. Four additional patients are currently alive and awaiting intracardiac repair.
The TOF repair, either primary or staged, was completed by a transatrial approach in 6 patients (2%). A combined transatrial-transpulmonary approach with limited infundibular patch plasty was performed in 65 patients (21.8%), therefore preserving pulmonary valve competence. The infundibular incision was extended across the pulmonary annulus in 207 patients (69.5%), with monocusp transannular patching in 10. Conduit interposition between the RV and the pulmonary bifurcation was performed in 20 patients (6.7%). The surgical technique for TOF repair did not differ between syndromic and nonsyndromic patients (Table 1).
Intracardiac repair was associated with additional cardiac surgical procedures in 73 patients (24.5%), including branch PA plasty (55), closure of additional muscular VSD (5), VSD enlargement (1), correction of partially anomalous pulmonary venous connection (1), aortopulmonary window repair (1), ligation of a systemic-to-pulmonary collateral (1), ligation of left persistent superior vena cava to the left atrium (4), bidirectional Glenn anastomosis as part of one-and-half ventricle repair (2), resection of supramitral fibrous ring (2) and resection of subaortic fibromuscular ring (1). A patent foramen ovale was suture-closed in 214 patients and left open in 84. Mean bypass and cross-clamp times were, respectively, 158 ± 63 minutes and 79 ± 33 minutes.
Mortality
Overall mortality was 6.5% (20/306). Six nonsyndromic and eight syndromic patients died early after primary (13) or staged (1) repair of TOF, while interstage attrition in syndromic patients accounted for three additional deaths after initial palliation. Three late deaths occurred in one syndromic and two nonsyndromic patients, after primary repair of their cardiac lesions.
Nonsyndromic Patients
Primary Repair. Early mortality after primary TOF repair in nonsyndromic patients was 3.1% (6/196). Right ventricular failure was the dominant cause of death in 4 patients, while a restrictive VSD with RV hypertrophy led to severe diastolic dysfunction in 2 patients. Two late deaths occurred 62 and 68 months after primary repair. The first child developed mediastinitis and residual VSD after repair of TOF and resection of a supramitral fibrous ring. Successful secondary closure of the residual VSD was accomplished. Five years later he was admitted to the emergency room with massive hemoptysis and hypotension. Cardiac catheterization demonstrated a ruptured pseudoaneurysm of the RV outflow patch. Emergency pseudoaneurysm repair was accomplished but fatal cerebral ischemia occurred. The second late death occurred in a 7 year old boy with TOF and multiple VSDs, six years after primary transannular patch repair and transatrial closure of an accessory apical VSD. Apical exclusion of the RV and recurrence of muscular VSD mandated surgical reintervention with recruitment of the RV apex, patch closure of two muscular VSDs, and RVOT reconstruction with pulmonary valved homograft. The postoperative course was complicated by fatal right hemispheric cerebral hemorrage.
Interstage Attrition. There was no attrition in palliated nonsyndromic patients awaiting complete repair.
Staged Repair. There was no mortality in 21 nonsyndromic patients undergoing TOF repair after initial palliation.
Syndromic Patients
Primary Repair. Hospital mortality after primary repair in syndromic patients was 10% (7/70). Right ventricular failure (3) and gram negative sepsis (4) were the dominant causes of death. Sepsis occurred as the final event in a clinical scenario dominated by low cardiac output in 3 patients. Underestimation of native PA hypoplasia contributed to early death in one patient with VACTERL syndrome, after primary transannular TOF repair with extensive left PA plasty. Persistent systemic RV pressure prompted a postoperative cardiac catheterization which showed residual hypoplasia of the distal pulmonary arterial tree (Nakata index 110 mm2/m2). The PA bifurcation was disconnected from the RV, the VSD patch removed, and a 4.0 mm right modified BT shunt was constructed after extensive hilum-to-hilum PA patch plasty. The child died 3 days later because of persistent low output and renal failure.
One late death occurred in another child with cystic fibrosis, 7 months after repair of TOF and aortopulmonary window. Her postoperative course was complicated by obstructive pulmonary desease that prompted the bronchoscopic diagnosis of distal tracheal stenosis. She underwent tracheal patch plasty and stent placement in the right main bronchus. She was successfully extubated but died 2 months later in an outside hospital due to respiratory failure.
Interstage Attrition. Mortality after palliation in syndromic patients was 20% (3/15 patientsts). Pulmonary overcirculation contributed significantly to heart failure in 2 early deaths. Hepatic failure was the cause of death in another patient with Alagille syndrome, 31 days after palliation by interposition of a valved conduit between the RV and the PA bifurcation, leaving the VSD open.
Staged Repair. Mortality after staged repair of TOF in syndromic patients was 9% (1/11 patients). This fatality occurred in a patient with VACTERL syndrome, who underwent repair 8 months after initial palliation by central shunt construction. Branch PA stenosis occurred, requiring patch plasty at the time of transannular repair. The postoperative course was complicated by multiorgan failure and the child died 3 weeks later because of enterocolitis.
Actuarial survival at 10.4 years was 94.1 ± 2.3% in nonsyndromic TOF and 84.3 ± 4.2% in syndromic TOF (p < 0.001) (Fig 1). Primary and staged repair allowed similar 10-year survival in the overall cohort (92.5 ± 2.0% vs 89.3 ± 5.1%, p = 0.35). There was a significant correlation between PA hypoplasia and the presence of a genetic syndrome (Table 1). The presence of PA hypoplasia and multiple cardiac and noncardiac anomalies stratified among the various genetic syndromes is depicted in Table 2. When the potential risk factors for death, identified by univariate analysis (Table 3) were entered in a Cox proportional hazard model, presence of a genetic syndrome and PA hypoplasia were identified as independent predictors of mortality (Table 4). A Kaplan-Meier survival analysis was conducted on the subgroup of 266 patients with normal PA anatomy, including 66 syndromic and 201 nonsyndromic TOF. Primary repair in the presence of normal PA anatomy resulted in significantly higher survival in nonsyndromic (96.4 ± 1.9%) compared with syndromic TOF (89.0 ± 3.9%) (p = 0.002) (Fig 2). The difference in survival probability between syndromic and nonsyndromic patients with TOF and normal PAs was indeed significant at 30 days follow-up (p = 0.004). Logistic regression confirmed genetic syndrome (p = 0.011, odds ratio [OR] = 9.8) as the main risk factor for early mortality in the subgroup of TOF with normal PAs, while complete closure of PFO reached borderline significance (p = 0.07, OR = 4.9). A secondary analysis was performed on the group of 85 syndromic patients and demonstrated a different impact of the various genetic syndromes on surgical outcome. Kaplan-Meier analysis indicated a significantly better survival for patients with del22q11 and trisomy 21 compared with VACTERL and other less common genetic syndromes (Fig 3). Logistic regression confirmed PA hypoplasia and surgical intervention for extracardiac anomalies as risk factors for mortality in the syndromic subgroup (Table 5 ).
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2 p value = 0.039), which accounted for an intensive care unit stay twice as long compared with nonsyndromic patients (7.4 ± 2.4 days vs 2.9 ± 1.1 days, p = 0.017). A complete review of postoperative complications in syndromic and nonsyndromic TOF is depicted in Table 6.
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Comment |
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TopAbstractIntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
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In our cohort of 306 patients with TOF and pulmonary stenosis, a proven or likely genetic defect was documented in over 27%, confirming the frequent association with TOF. Our analysis shows the following.
This retrospective study has several limitations. Preoperative diagnosis was based on routine 2D echocardiography. Cardiac catheterization was selectively performed to validate echocardiographic findings suggesting PA hypoplasia, multiple VSDs, or anomalous coronary patterns. Therefore, the Nakata index was calculated in a limited number of patients. Nevertheless, only one patient required repair take-down for incorrect preoperative evaluation of the pulmonary arterial tree dimensions by 2D echocardiography.
In the absence of a randomized study, it could be argued that palliative surgery was selected for the patients at higher risk, such as the syndromic TOF, introducing a selection bias in the analysis. Surgical technique was clearly tailored to the individual anatomy, according to the degree of RVOT obstruction and PA arborization pattern. However, no statistical difference was documented when comparing surgical stategy or technique of repair in syndromic versus nonsyndromic TOF. Primary and staged repair allowed similar 10-year survival in the overall cohort. We infer that anatomy, not genetics, should guide a surgical strategy of primary or staged TOF repair, despite the absolute higher mortality observed in the syndromic TOF.
In conclusion, pulmonary arborization defects and genetic syndromes other than del22q11 or trisomy 21 are associated with a worse outcome after repair or palliation of TOF. Beyond the neonatal period, primary complete repair of TOF in syndromic patients with normal PA anatomy appears to be a valid surgical strategy, with no additional risk for mortality and higher freedom from reintervention.
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= nonsyndromic; 
= syndromic.)
= Down; 
= VACTERL.)
