Outcomes of Multistage Palliation of Infants With Single Ventricle and Atrioventricular Septal Defect

Abstract

Background:

Published palliation outcomes of infants with functional single ventricle (SV) and common atrioventricular septal defect (AVSD) are poor due to associated cardiac and extracardiac anomalies and development of atrioventricular valve (AVV) regurgitation. We report current palliation results.

Methods:

From 2002 to 2012, 80 infants with functional SV with AVSD underwent multistage palliation. Competing-risks analyses modeled events after first-stage surgery and Glenn (death/transplantation vs next palliation surgery) and examined factors associated with survival and AVV intervention.

Results:

Sixty-eight (80%) patients received neonatal palliation: modified Blalock-Taussig shunt (n = 33, 41%), Norwood (n = 20, 25%), and pulmonary artery band (n = 15, 19%), whereas 12 (15%) received primary Glenn. On competing-risks analysis, one-year following first-stage surgery, 29% of patients had died or received transplantation and 62% had undergone Glenn. Five years following Glenn, 9% of patients had died or received transplantation and 68% had undergone Fontan. Overall eight-year survival was 64% and was lower in patients with genetic syndromes (53% vs 82%), patients requiring concomitant total anomalous pulmonary venous connection repair (53% vs 69%), and those requiring neonatal palliation (48% vs 100%). Factors associated with mortality were unplanned reoperation (hazard ratio [HR]: 3.7 [1.7-8.0], P = .001) and extracorporeal membrane oxygenation use (HR: 7.1 [3.0-16.6], P < .001). Initial AVV regurgitation ≥ moderate was associated with AVV intervention (HR: 6.2 [2.4-16.1], P = .002) with eight-year freedom from death or AVV intervention of 25% in those patients.

Conclusions:

Patients with SV with AVSD are a distinct group and commonly have associated cardiac and extracardiac malformations that complicate care and affect survival. The development of AVV regurgitation requiring intervention is common but does not affect survival.

Keywords

atrioventricular septal defect (AVSD)Norwood procedure heterotaxy palliation Fontan cavopulmonary anastomosis

Introduction

Complete atrioventricular septal defect (AVSD) is a common anomaly that represents almost 7% of all congenital heart defects.¹ Although the majority of patients with AVSD are considered balanced and have two well-formed ventricles and atrioventricular valves (AVVs), less than 10% of patients with AVSD have unbalanced defects with the common AVV sitting more over one ventricle than the other, often with significant hypoplasia of the contralateral ventricle.^2

–5 In those patients, intracardiac repair is not possible and therefore single ventricle (SV) palliation is performed.^5,6 In addition to patients with severe unbalanced AVSD, a number of patients have complex associated cardiac lesions and are considered to have functional SV that is not amenable to biventricular intracardiac repair and therefore SV palliation is performed. An example of those patients includes those with straddling AVV, associated double outlet right ventricle with multiple ventricular septal defects, or noncommitted ventricular septal defect.⁷

Functional SV with AVSD comprises less than 10% of all SV cardiac malformations. This is a heterogeneous anomaly with different associated cardiac lesions and various degrees of systemic or pulmonary outflow obstruction.^2,4
–6 Consequently, the initial SV palliative surgery varies based on anatomy and might include the Norwood operation in patients with severe systemic outflow obstruction, modified Blalock-Taussig shunt (BTS) in patients with restrictive pulmonary blood flow, or pulmonary artery band (PAB) in patients with unrestrictive pulmonary blood flow, which can also be combined with coarctation repair in some patients as indicated.^{2

–10} Furthermore, a number of patients with functional SV with AVSD have a balanced circulation that allows deferral of first-stage palliation to a later stage and those receive a primary Glenn bidirectional cavopulmonary shunt as their initial palliative surgery.¹¹

Reported palliation outcomes of SV with AVSD have been poor and SV with AVSD has been shown to be a risk factor following Norwood, BTS, PAB, or Glenn.^{5
–7,9
–11} In many series, reported palliation outcomes of SV with AVSD were even inferior to those of hypoplastic left heart syndrome.^{5
–7,9,10,12} Those inferior outcomes have been attributed to the complexity of the cardiac anomaly and presence of associated cardiac lesions, to the development of AVV regurgitation with subsequent need for AVV intervention, and to the high prevalence of genetic syndromes and associated extracardiac anomalies that contribute to operative morbidity and complicate outpatient management.^{5,6,8,13

–16} We aim in the current series to examine early and late results following palliation of SV with AVSD and to assess factors affecting outcomes with focus on survival and need for AVV intervention.

Patients and Methods

Inclusion Criteria

Between 2002 and 2012, 80 consecutive infants with functional SV and AVSD underwent their first palliative surgery at Children’s Healthcare of Atlanta, Emory University. Patients were identified using our institutional surgical database. Demographic, morphologic, clinical, operative, and hospital details were abstracted from the medical records for analysis. Approval of this study was obtained from our hospital’s institutional review board and requirement for individual consent was waived for this observational study.

Echocardiographic Data Collection and Definitions

The definition of unbalanced AVSD is complex and is made based on various parameters including the size of the ventricles and the AVV index (AVVI), measured by dividing the left AVV area over the total AVV area. By definition, patients with unbalanced AVSD to the right (dominant ventricle of right morphology) have AVVI <0.4 and patients with unbalanced AVSD to the left (dominant ventricle of left morphology) have AVVI >0.6.^2
–4,17,18 Left-sided obstruction lesions such as subaortic obstruction, aortic valve hypoplasia, small ascending aorta, aortic arch hypoplasia, and coarctation of the aorta can be present in patients with dominant right ventricle; while pulmonary outflow obstruction can be present in patients with dominant left ventricle.

Based on the echocardiogram reports, all patients in our current series were considered to have functional SV with AVSD and were referred for multistage single stage palliation. In this study, we included patients who were labeled to have significant unbalanced AVSD (n = 68) in addition to patients who had two well-formed ventricles with mild unbalance; however, they were not thought to be amenable to septation due to the presence of noncommitted ventricular septal defect, multiple ventricular septal defects, straddling of the AVV, or very complex anatomy (n = 12). It is very plausible that, during the same study period, several infants with mild form of unbalanced AVSD (AVVI < 0.4 or > 0.6) underwent biventricular repair at our institution; however, our retrospective echocardiographic review was performed only on patients who were referred for SV palliation, in adherence with the purpose of this study.

Finally, patients were considered to have heterotaxy syndrome based on the recent Society of Thoracic Surgeons nomenclature review and classification that defined heterotaxy syndrome as an abnormality where the internal thoracoabdominal organs demonstrate abnormal arrangement across the left-right axis of the body.¹³ Left atrial isomerism was defined as a subset of heterotaxy where some paired structures on opposite sides of the left-right axis of the body are symmetrical mirror images of each other and have the morphology of the normal left-sided structures. Right atrial isomerism was defined as a subset of heterotaxy where some paired structures on opposite sides of the left-right axis of the body are symmetrical mirror images of each other and have the morphology of the normal right-sided structures.¹⁴

Follow-Up

Time-related outcomes were determined from recent office visits documented in the electronic chart of Children’s Healthcare of Atlanta system or from direct correspondence with pediatric cardiologists outside the system. Mean follow-up duration was 5.5 ± 4.2 years and was 93% complete.

Statistical Analysis

Data are presented as means with standard deviation, medians with interquartile ranges (IQRs), or frequencies and percentages, as appropriate. Time-dependent outcomes after first-stage palliation surgery and after Glenn was parametrically modeled. Parametric probability estimates for time-dependent outcomes use models based on multiple overlapping phases of risk using PROC HAZARD (available for use with the SAS system at https://www.lerner.ccf.org/qhs/software/hazard/). The HAZARD procedure uses maximum likelihood estimates to resolve risk distribution of time to event in up to three phases of risk (early decreasing or peaking hazard, constant hazard, and late increasing hazard). Maximum likelihood estimates are iteratively calculated using nonlinear optimization-based algorithms. Smoothed survival curves were generated using the HAZPRED procedure in SAS. PROC HAZPRED computes predictions for the survivorship and hazard functions along with their confidence limits.

Competing risks analysis was performed to model the probability over time of the two mutually exclusive end points after first-stage palliation surgery: death or transplantation and survival to Glenn. After the Glenn, competing risks analysis was performed to model two mutually exclusive end points after Glenn: death or transplantation and survival to Fontan. To identify risk factors associated with death or transplantation following first-stage palliation surgery, parametric survival models were constructed using one risk factor at a time. Given the limited sample size available for analysis, multivariable models were not considered. Similar analyses were performed to identify risk factors associated with overall mortality following initial surgery and risk factors for AVV intervention. Effects of covariates on the probability of outcomes in survival models are given as hazard ratio (HR) with 95% confidence interval. All statistical analyses were performed using SAS version 9.3 (The SAS Institute, Cary, North Carolina). A P < .05 was considered statistically significant.

Results

Patients’ Characteristics, Morphologic, and Operative Details

Eighty infants with SV with AVSD underwent their initial palliation surgery. There were 48 males (60%). Median age at surgery was eight days (IQR = 5-49) and median weight was 3.1 kg (IQR = 2.6-3.5) with 17 (21%) patients ≤ 2.5 kg. There were 17 (21%) patients who were born prematurely ≤ 36 weeks of gestation. Sixty-three (79%) patients had associated genetic syndromes including heterotaxy (n = 53), Down (n = 6), Klinefelter (n = 1), CHARGE (n = 1), Mowat-Wilson (n = 1), and cri-du-chat (n = 1). In patients with heterotaxy, 37 (70%) of 53 had right atrial isomerism while 16 (30%) of 53 had left atrial isomerism. Associated major extracardiac anomalies requiring intervention at the same hospitalization were present in those patients with genetic syndromes and included intestinal malrotation requiring the Ladd procedure (n = 10), duodenal atresia (n = 2), biliary atresia (n = 1), Hirschsprung’s (n = 1), and hydrocephaly (n = 1).

Echocardiographic examination of those patients showed that the dominant ventricle morphology was right (n = 45, 56%), left (n = 23, 29%), or two well-formed ventricles with mild unbalance (n = 12, 15%). Fifty-one (64%) patients had double outlet right ventricle. Overall, 29 (36%) patients had total anomalous pulmonary venous connection (TAPVC). The TAPVC type was supracardiac (n = 13/29, 43%), cardiac (n = 7/29, 24%), infracardiac (n = 5/29, 17%), or mixed (n = 4/29, 14%); with 8 (28%) of 29 having obstructed drainage at time of initial presentation. Antegrade pulmonary blood flow was absent in 14 (18%), restricted in 29 (36%), and unrestricted in 37 (46%). Aortic arch obstruction was present in 26 (33%) patients, while aortic annulus hypoplasia was present in 22 (28%) patients. Seventeen (21%) patients had interrupted drainage of the inferior vena cava and 33 (41%) had bilateral superior vena cava. The AVV regurgitation at preoperative echocardiographic assessment was graded trivial (n = 28, 35%), mild (n = 38, 48%), moderate (n = 10, 13%), and severe (n = 4, 5%).

Sixty-eight (85%) patients required neonatal first-stage palliation including BTS (n = 33, 41%), Norwood (n = 20, 25%), and PAB (n = 15, 19%) including 6 of 15 who required concomitant coarctation repair. In the remaining 12 (15%) patients, primary Glenn bidirectional cavopulmonary shunt was the initial palliative surgery. In neonates who underwent Norwood, the source of pulmonary blood flow was BTS (n = 4) or Sano shunt (n = 16). Concomitant surgery at time of palliation was performed in 36 (45%) patients and included 38 procedures: TAPVC repair (n = 16), pulmonary artery augmentation (n = 10), aortic coarctation repair (n = 6), AVV repair (n = 5), and pacemaker implantation (n = 1).

Early Hospital Outcomes

Following surgery, eight (10%) patients required extracorporeal membrane oxygenation (ECMO) support. Among those, three of eight were following TAPVC repair and BTS, one of eight was following TAPVC repair and AVV repair and BTS, one of eight was following BTS and pulmonary artery augmentation, two of eight following Norwood, and one of eight following Norwood and AVV repair. Hospital survival for patients who required ECMO support was two (25%) of eight. Interestingly, the two hospital survivors did not have heterotaxy while the remaining six patients who did not survive all had heterotaxy.

Twelve (18%) patients required early unplanned reoperations during the same hospital admission. Among those, 4 of 12 were following BTS and TAPVC repair (2 for tying of the main pulmonary artery due to overcirculation, 1 for shunt revision, and 1 for removal of left atrial clots), 1 of 12 was following BTS for shunt revision, 1 of 12 was following PAB and TAPVC repair for addition of shunt, 5 of 12 were following PAB (1 for addition of shunt, 1 for tightening of a band, 2 for Norwood operation sue to the development of subaortic obstruction, 1 for heart transplantation), and 2 of 12 following Norwood (1 for replacement of the AVV and 1 for addition of BTS to a patient who originally had a Sano shunt). Hospital survival for patients who underwent unplanned reoperation was 9 (75%) of 12. Overall, hospital mortality occurred in 15 (19%) patients including 8 of 15 following BTS, 3 of 15 following PAB, and 4 of 15 following Norwood. Among those, 9 (60%) of 15 had concomitant TAPVC repair and 3 (20%) of 15 had concomitant AVV repair plus 1 of 15 had separate AVV replacement following Norwood.

Competing Risks Analysis Following First-Stage Palliation Surgery

Following the 68 neonatal first-stage surgeries, hospital mortality occurred in 15 (22%) and 53 (68%) were discharged alive. There were seven (10%) additional interstage mortalities prior to Glenn, while one (1%) patient received heart transplantation and 1 (1%) patient continues having a band in a balanced circulation. The remaining 44 (65%) patients progressed to receive Glenn shunt.

Competing risks models showed that the proportion of patients who underwent Glenn started to rise around three months and peaked around seven months following first-stage palliation. The hazard function for death or transplantation prior to Glenn was characterized by the presence of an early risk phase during the initial six months that decreased gradually until it disappeared around one year after surgery. Competing risks analysis showed that at six months following first-stage palliation surgery, 27% of patients had died or received transplantation, 32% had undergone Glenn, and 41% were alive awaiting Glenn. At 1 year, 29% of patients had died or received transplantation, 62% had undergone Glenn, and 9% were alive awaiting Glenn (Figure 1).

Figure 1.

Competing risks analysis of outcomes after first-stage palliation surgery in 68 neonates with SV with AVSD. AVSD indicates atrioventricular septal defect; SV, single ventricle.

Factors associated with death or transplantation prior to Glenn were explored and are presented in Table 1. There was a trend for increased risk of death or transplantation prior to Glenn that did not reach statistical significance in patients who received concomitant TAPVC and those who underwent unplanned cardiac reoperation. The only factor that was significantly associated with death or transplantation prior to Glenn was postoperative ECMO use.

Table 1.

Univariable Analysis of Death or Heart Transplantation Following First-Stage Palliation in Neonates With SV With AVSD.

Risk Factor	Hazard Ratio	95% CI	P Value
Gender, female	1.53	0.64-3.67	.342
Age, days	0.98	0.95-1.01	.247
Weight ≤ 2.5 kg	0.97	0.92-1.03	.954
Weight, kg	1.33	0.74-2.52	.379
Genetic syndromes	4.72	0.63-35.22	.131
Heterotaxy vs none	4.84	0.64-8.93	.126
Nonheterotaxy vs none	2.03	0.19-37.04	.554
Initial palliation type
BTS vs Norwood	1.38	0.48-3.92	.552
PAB vs Norwood	1.08	0.30-3.85	.911
Dominant ventricle
Two ventricles vs right	1.70	0.62-4.64	.300
Left vs right	0.77	0.27-2.21	.631
Concomitant TAPVC	2.12	0.89-5.09	.093
Initial AVV regurgitation (moderate/severe vs mild/trace)	0.89	0.26-3.10	.859
Unplanned reoperation	2.42	0.93-6.30	.070
ECMO	7.52	3.00-18.84	<.001

Abbreviations: AVSD, atrioventricular septal defect; AVV, atrioventricular valve; BTS, Blalock-Taussig shunt; CI, confidence interval; ECMO, extracorporeal membrane oxygenation; PAB, pulmonary artery band; SV, single ventricle; TAPVC, total anomalous pulmonary venous connection.

Outcomes Following Glenn

Overall, 56 patients received the Glenn shunt; 44 following first-stage palliation surgery and 12 primary Glenn. Among those, 21 (38%) of 56 had bilateral Glenn shunts. Of note, 10 (18%) of 56 had interrupted inferior vena cava and hence they received the Kawashima procedure. Additional surgeries at time of Glenn were required in 23 patients and included pulmonary artery augmentation (n = 13), AVV repair (n = 8), TAPVC repair (n = 5), Damus-Kaye-Stansel anastomosis (n = 4), pacemaker implantation (n = 1), atrial septectomy (n = 1), and aortic arch augmentation (n = 1).

Following Glenn in those 56 patients, 39 (70%) patients underwent Fontan, 6 (10%) died before Fontan, and 11 (20%) were alive and considered proper Fontan candidates (including 10 patients who had Kawashima). Concomitant surgery at time of Fontan included AVV repair (n = 9), pulmonary artery augmentation (n = 6), pulmonary venous stenosis repair (n = 2), atrial septectomy (n = 1), and pacemaker implantation (n = 1).

Competing risks models showed that the proportion of patients who underwent Fontan started to rise around 1.5 years and peaked around 2.5 years following Glenn. The hazard for death or transplantation showed a gradual steady increase over time with largest risk occurring within the first six months. Competing risks analysis showed that at two years following Glenn, 6% of patients had died or received transplantation, 23% had undergone Fontan, and 71% were alive awaiting Fontan. At five years, 9% of patients had died or received transplantation, 68% had undergone Fontan, and 23% were alive awaiting Fontan (Figure 2).

Figure 2.

Competing risks analysis of outcomes after Glenn in 56 neonates with SV with AVSD. AVSD indicates atrioventricular septal defect; SV, single ventricle.

Overall Survival and Risk Factors

Parametric survival estimates for the entire cohort following surgery were 88% (79%-92%), 71% (61%-79%), and 64% (53%-73%) at one month, one year, and eight years. The hazard function for death after surgery was characterized by the presence of an early risk phase during the initial one year following surgery and a low late risk phase that continued following surgery with low attrition with time (Figure 3).

Figure 3.

Time-dependent survival following initial palliation surgery in 80 infants with SV with AVSD. The solid lines in the parametric model represent parametric point estimates and the dashed lines enclose the 95% confidence interval. Circles represent nonparametric estimates. AVSD indicates atrioventricular septal defect; SV, single ventricle.

Risk factors affecting overall survival were examined and are presented in Table 2. Risk factors for overall mortality were ECMO use (HR: 7.1 [3.0-16.6], P < .001) and unplanned reoperation (HR: 3.7 [1.7-8.0], P = .001). Given the numerous associated variables and the small cohort size, survival analysis was limited and did not detect significant demographic or anatomic risk factors. However, survival seemed to be inferior in patients who required concomitant TAPVC repair (53% vs 69% at eight years), those with genetic syndromes (52% for heterotaxy vs 55% for nonheterotaxy genetic syndromes vs 82% for no genetic syndromes at eight years; Figure 4A and B). Of note, survival was 100% in patients who underwent primary Glenn shunt while it was not significantly different between patients who underwent the various first-stage palliation surgeries (55% following Norwood, 43% following BTS, 43% following PAB at eight years). Interestingly, neither the dominant ventricle morphology nor the presence of AVV regurgitation equal or more than moderate affected survival in our patent cohort (Figure 5A and B).

Table 2.

Univariable Analysis of Overall Survival Following Surgery in Neonates With SV With AVSD.

Risk Factor	Hazard Ratio	95% CI	P Value
Sex, female	1.85	0.89-3.84	.097
Age, days	0.98	0.96-1.00	.033
Weight ≤ 2.5 kg	1.21	0.52-2.83	.661
Weight, kg	0.76	0.52-1.12	.166
Genetic syndromes	2.79	0.84-9.21	.093
Heterotaxy vs none	2.67	0.80-9.01	.109
Nonheterotaxy vs none	3.21	0.77-13.51	.111
Dominant ventricle
Two ventricles vs right	1.35	0.50-3.70	.554
Left vs right	0.95	0.41-2.23	.910
Concomitant TAPVC	1.73	0.83-3.59	.143
Initial AVV regurgitation (moderate/severe vs. mild/trace)	1.02	0.39-2.69	.965
Unplanned reoperation	3.71	1.71-8.03	.001
ECMO	7.11	3.04-16.64	<.001

Abbreviations: AVSD, atrioventricular septal defect; AVV, atrioventricular valve; CI, confidence interval; ECMO, extracorporeal membrane oxygenation; SV, single ventricle; TAPVC, total anomalous pulmonary venous connection.

Figure 4.

Parametric model for survival following initial palliation surgery in 80 infants with SV with AVSD stratified by (A) concomitant TAPVC repair and (B) presence of genetic syndromes. AVSD indicates atrioventricular septal defect; SV, single ventricle; TAPVC, total anomalous pulmonary venous connection.

Figure 5.

Parametric model for survival following initial palliation surgery in 80 infants with SV with AVSD stratified by (A) dominant ventricle morphology and (B) the degree of AVV regurgitation on initial echocardiogram. AVSD indicates atrioventricular septal defect; AVV, atrioventricular valve.

Freedom From AVV Intervention

Overall, 20 patients underwent 25 AVV interventions. Five patients had AVV repair with their first-stage palliation surgery; and among those, three died in the hospital (two after BTS and one after Norwood)and two are late survivors (one without AVV reoperation and one received two subsequent AVV repairs at time of Glenn and Fontan). Additionally, 1 patient had attempted AVV repair then replacement during the same admission after Norwood and died in the hospital. At time of Glenn, eight patients had AVV repair (one had prior repair and seven had their first AVV repair). Among those, one died after Glenn, one had AVV replacement and died after that procedure, one had sudden late death at home, one had additional AVV repair at time of Fontan and is alive, and four are alive after Fontan without AVV reoperations. At time of Fontan, nine patients had AVV repair (two had prior repair and seven had their first AVV repair). All of those patients are alive without AVV reoperation.

Freedom from AVV intervention was 92% (84%-96%), 83% (73%-90%), and 75% (63%-84%) at one month, one year, and eight years. Several anatomic, demographic, and surgical variables associated with AVV intervention were explored and the only factor associated with the need for AVV intervention was initial AVV regurgitation equal or more to moderate (HR: 6.2 [2.4-16.1], P = .002; Figure 6). Although the presence of AVV regurgitation equal or more than moderate did not affect survival, the freedom from death or AVV intervention in patients who had AVV regurgitation equal or more than moderate on initial echocardiogram was 25% versus 57% in those who did not (HR: 2.5 [1.2-5.1], P = .012; Figure 7).

Figure 6.

Time-dependent freedom from AVV intervention following surgery in 80 infants with SV with AVSD. The solid lines in the parametric model represent parametric point estimates and the dashed lines enclose the 95% confidence interval. Circles represent nonparametric estimates. AVSD indicates atrioventricular septal defect; AVV, atrioventricular valve; SV, single ventricle.

Figure 7.

Time-dependent freedom from death or AVV intervention following surgery in 80 infants with SV with AVSD stratified by the degree of AVV regurgitation on initial echocardiogram. AVSD indicates atrioventricular septal defect; AVV, atrioventricular valve; SV, single ventricle.

Discussion

Our study demonstrated eight-year survival following SV with AVSD palliation of 64%. After exclusion of infants who received primary Glenn, eight-year survival approached 50% following neonatal first-stage palliation (55% after Norwood, 43% after BTS or PAB). Those results are inferior to our own institution’s experience in neonates with other SV anomalies. For example, eight-year survival following Norwood in neonates with hypoplastic left heart syndrome at our institution during the exact same period was 66%, demonstrating that despite current advances in the perioperative care of SV patients, management of SV with AVSD patients continues to be challenging and associated with lower survival.¹⁹ The inferior palliation results in neonates who have SV with AVSD are not limited to those undergoing Norwood. In previous reports from our institution following SV palliation with PAB in patients with unrestricted pulmonary blood flow or BTS in patients with restricted pulmonary blood flow, underlying cardiac anomaly of functional SV with AVSD was an independent factor associated with inferior survival.^9,10 We didn’t notice an era effect on survival in our current series that spanned over 11 years. Interestingly, in a recent series from Australia that spanned over 40 years, outcomes were nearly identical to those in our series and there was no significant era effect on survival.¹²

There is a high association between SV with AVSD and genetic syndromes.^3,5,6 In our series, 79% of those patients had associated genetic syndromes with heterotaxy being the most common, followed by Down syndrome. This is clearly a higher prevalence of genetic syndromes than in other forms of SV anomalies (less than 15%).^19
–21 The presence of genetic syndromes has been clearly linked to more complicated hospital course and higher operative mortality following neonatal cardiac surgery in general. In addition, the effect of genetic syndromes on survival following congenital cardiac surgery has been noted to extend beyond the operative period with continuous attrition risk that persisted for at least a year following initial cardiac surgery.²² We recently studied the effects of genetic syndromes on palliation outcomes in neonates born with SV anomalies. We noted that genetic syndromes were associated with longer durations of mechanical ventilation, intensive care unit stay, and hospital stay following first-stage palliation, in addition to higher hospital mortality, lower progression to subsequent Glenn, and lower overall survival. Those inferior results are likely related to the presence of extracardiac anomalies in patients with genetic syndromes and the higher association of additional risk factors such as low weight and prematurity that are more prevalent in patients with genetic syndromes.²³

The most common genetic syndrome in our series was heterotaxy. Many previous reports have shown that heterotaxy was associated with increased mortality risk following various palliative procedures including BTS, Norwood, or PAB.^{6

–10,14,15,24
–26} A recent Society of Thoracic Surgeons study examining hospital survival of 1,505 patients with heterotaxy who underwent surgery demonstrated that discharge mortality was higher in patients with heterotaxy compared to patients without heterotaxy for every procedure mortality risk category and for different subgroups of patients such as those who underwent BTS or Fontan.¹⁴ Several recent single institution reports of palliation outcomes in patients with heterotaxy demonstrated increased mortality, respiratory complications, and more complicated postoperative course.^{14,15,24,26,27} Several factors have been linked to the increased postoperative morbidity in heterotaxy patients. The increased respiratory complications might be related to airway ciliary dyskinesia. In addition, heterotaxy patients often have other extracardiac malformations such as intestinal malrotation that might require surgery with subsequent risk of abdominal complications and asplenia with the subsequent risk of sepsis.^{14,15,24,26

–30} In addition to the presence of extracardiac anomalies in patients with heterotaxy, the complexity of the intracardiac anatomy with the common presence of TAPVC, AVV regurgitation, pulmonary atresia, arrhythmia, and heart block is vastly related to the higher operative mortality.^{14,15,24,26,31
–33} At our institution, the presence of heterotaxy was associated with more complicated postoperative course and higher hospital mortality compared to other SV patients. However, subsequent to discharge, interstage mortality, progression to subsequent Glenn, and overall survival in hospital survivors seemed comparable to other SV patients indicating that the initial perioperative period is the most challenging in those patients.²⁶

The second common genetic syndrome in neonates who have SV with AVSD was Down syndrome. Similar to heterotaxy, patients with Down have common extracardiac anomalies that contribute to their morbidity including gastrointestinal problems (Hirschsprung’s disease, duodenal atresia, etc) and most importantly obstructive sleep apnea complicating early and late management. The chronic hypoventilation in Down patients is also associated with the development of elevated pulmonary vascular resistance leading to disqualification from progression toward the Fontan circulation or higher mortality following Fontan.^16,34,35 Among seven Down patients in our current series, one died after unplanned reoperation and conversion from PAB to Norwood and three more died prior to Glenn. At last follow-up, there were three survivors, two of whom had undergone Glenn with subsequent takedown to BTS due to pulmonary hypertension and are not expected to be long-term survivors, and one who had undergone Glenn but is not considered a proper Fontan candidate due to elevated pulmonary vascular resistance and obstructive sleep apnea. Those poor palliation outcomes in patients with Down syndrome are even more pronounced than those with heterotaxy, likely due to the ongoing mortality and morbidity beyond the perioperative period owing to the development of pulmonary vascular obstructive disease. Single ventricle palliation outcomes in Down patients have traditionally been poor. In a recent large series of SV palliation in 28 Down patients from Texas, five-year survival was 61% (compared with 85% in non-Down nonheterotaxy patients with unbalanced AVSD).¹⁶ This is comparable to our series where eight-year survival in non-Down nonheterotaxy patients was 82% compared to 55% in those with nonheterotaxy genetic problems (the majority had Down syndrome). As stated earlier, a major cause of the late mortality was the development of elevated pulmonary vascular resistance, and this is also similar to the findings from Texas where pulmonary vascular resistance higher than 3 Wood units × m² was an independent risk factor for mortality.¹⁶

Concomitant TAPVC repair was associated with increased operative mortality in our series, especially when performed for obstructed TAPVC during neonatal palliation.^{8
–10,24,36
–38} Total anomalous pulmonary venous connection repair in SV patients is especially challenging and has been repeatedly shown to be associated with significantly worse early and late outcomes than those following simple TAPVC repair. Part of the challenge is due to the inability to accurately predict the amount of native pulmonary outflow obstruction except for patients with pulmonary atresia, the existence of varying degrees of lung pathology, and elevated pulmonary vascular resistance in patients with obstructed TAPVC that complicate recovery following BTS and compromise the ability to perform adequate PAB.^{8
–10,24,36
–38} While concomitant repair is necessary in neonates with obstructive TAPVC, a delay of TAPVC repair to second-stage operation in those with nonobstructive TAPVC might be associated with improved survival in appropriate patients.

In the current study, dominant ventricle morphology was not associated with survival. Of importance, however, many of the mortalities in patients with two well-formed ventricles were during first-stage palliation and were in patients who received concomitant TAPVC repair. This higher early mortality likely contaminates our ability to assess whether those patients do better long-term than those with severe unbalance of the left or right ventricle.

The use of ECMO was highly associated with death and only 25% of patients who received postoperative ECMO in our series survived to hospital discharge. Extracorporeal membrane oxygenation use in SV has traditionally been associated with higher mortality; however, recent reports have shown improved survival of ECMO support in SV patients that was comparable to that in cardiac patients with two ventricle anomalies.^39,40 Nonetheless, while numbers are too small to detect statistical significance, the presence of heterotaxy syndrome or concomitant TAPVC repair has been anecdotally described to be associated with poor survival when ECMO was needed. This is also noted in our series where all patients with heterotaxy who required ECMO support died, similarly all patients who received TAPVC repair and required ECMO support died.^39,40

Atrioventricular valve regurgitation is common in SV with AVSD patients. Atrioventricular valve regurgitation is a known risk factor for early and late mortality following SV palliation.^32,33 In our series, the degree of AVV regurgitation on initial echocardiogram was naturally associated with early or late AVV intervention. Nonetheless, the degree of initial AVV regurgitation or the requirement for AVV intervention was not associated with increased mortality in our series. Timing of AVV repair is ideally delayed at least to Glenn stage. In our series, five patients underwent concomitant AVV repair at time of first-stage palliation surgery and one more during the same admission following Norwood and only two were hospital survivors. On the other hand, in patients who underwent AVV repair at time of subsequent operations, this was not associated with an increase in mortality. While volume unloading at time of Glenn might be associated with some improvement in AVV regurgitation, this is usually not the case in patients with AVSD because of the common presence of structural valve abnormalities that are not affected by volume unloading. It is our philosophy to perform AVV repair at time of Glenn if AVV regurgitation is moderate or more, especially that our experience with repair of common AVV has been favorable.

This study is subject to the limitations inherent in all retrospective observational studies such as selection bias and lack of randomization. As data of patients who underwent AVSD repair were not collected, this study is not designed to assess candidacy for biventricular repair. Additionally, the small cohort size and the multiple variables in this patient cohort might have limited the power of the study to identify clinically significant risk factors.

Summary

Despite the advances in all management aspects of SV anomalies, the treatment of neonates with functional SV with AVSD continues to be challenging and associated with low mid-term survival. Those patients commonly have genetic syndromes and extracardiac anomalies that are associated with increased early mortality risk following first-stage palliation surgery and diminished overall survival. In addition to extracardiac anomalies, SV anomalies with AVSD are commonly associated with additional cardiac lesions, most importantly TAPVC, that further complicate the care of those patients and decrease early and late survival. Several patients develop progressive AVV regurgitation requiring early or late surgical intervention. Neonatal AVV repair is often associated with high mortality; however, AVV repair at time of subsequent palliative stages is generally successful and associated with comparable survival to those who did not require AVV intervention.

Footnotes

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

Abbreviations and Acronyms

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