Intramural Ventricular Septal Defect Is a Distinct Clinical Entity Associated With Postoperative Morbidity in Children After Repair of Conotruncal AnomaliesClinical Perspective
Background—Intramural ventricular septal defects (VSDs) are interventricular communications through right ventricular free wall trabeculations that can occur after repair of conotruncal anomalies. We assessed the prevalence of residual intramural VSDs and their effect on postoperative course.
Methods and Results—Children who underwent biventricular repair of a conotruncal anomaly from January 1, 2006, to June 30, 2013, and had a postoperative transthoracic echocardiogram were included. Images were reviewed for residual intramural or nonintramural VSDs. The primary outcome was a composite of mortality, extracorporeal membrane oxygenation use, and need for subsequent catheter or surgical VSD closure. The secondary outcome was postoperative hospital length of stay. A residual VSD was present in 256 of the 442 subjects (58%), of which 231 (90%) were <2 mm in size. Forty-nine patients (11%) had intramural VSDs, and 207 (47%) had nonintramural VSDs. Patients with intramural VSDs were more likely to reach the primary composite outcome compared with those with nonintramural VSDs or no residual VSD (14 of 49 [29%] versus 15 of 207 [7%] versus 6 of 186 [3%]; P<0.0001). In addition, those with intramural VSDs had longer postoperative hospital length of stay compared with those with nonintramural VSDs or no residual VSD (20 days [interquartile range, 11–42 days] versus 7 days [interquartile range, 5–14 days] versus 6 days [interquartile range, 4–11 days]; P=0.0001). These associations remained significant after adjustment for known risk factors for poor outcomes, including residual VSD size and operative complexity.
Conclusions—Among residual VSDs after repair of conotruncal anomalies, intramural VSDs are uniquely associated with postoperative morbidity, mortality, and longer postoperative hospital length of stay. It is important to recognize intramural VSDs in the postoperative period.
An intramural ventricular septal defect (VSD) is a residual VSD that can be seen after surgical repair of conotruncal defects that involve patch closure of a VSD from the left ventricle to a great artery. The term intramural VSD was coined by Preminger et al1 in a brief report 20 years ago. Intramural VSD is defined as a tunnel-like communication that can occur when the VSD patch is not anchored to the right ventricular free wall but rather is attached to right ventricular trabeculations so that blood can flow around the VSD patch and into the right ventricular cavity (Figure 1).
Clinical Perspective on p 1394
Intramural VSDs have not been well studied since their first description,1 and little is known about their prevalence, associations, and impact on surgical outcome. The original case series by Preminger et al1 described 8 patients with intramural VSDs; all had right ventricular hypertension and underwent multiple unsuccessful reoperations. This series illustrated that intramural VSDs were distinct from other types of residual VSDs and could result in poor outcome. Another study found that 4 patients with no VSDs or only small VSDs visualized on intraoperative transesophageal echocardiogram were subsequently found to have large intramural VSDs requiring reoperation,2 suggesting that intramural defects may be challenging to identify intraoperatively and may enlarge over time. Finally, there has been 1 other case series in which 3 of 5 children with intramural VSDs required reoperation for VSD closure.3 These reports suggest that intramural VSDs are clinically important and may contribute to postoperative morbidity and mortality.
In this study, we sought to identify the prevalence of intramural VSDs in patients who have undergone biventricular repair of conotruncal defects and to determine whether intramural VSDs are associated with postoperative morbidity and mortality. We hypothesized that intramural VSDs were more likely to result in a worse outcome (reintervention, mortality, extracorporeal membrane oxygenation [ECMO] use) and longer postoperative hospital length of stay (PLOS) compared with nonintramural (peripatch or muscular) types of residual VSD.
We performed a retrospective cohort study of all children 0 to 18 years of age at our institution who underwent biventricular repair of a conotruncal anomaly from January 1, 2006, to June 30, 2013. Hospital Institutional Review Board approval was obtained, and waiver of consent was granted.
The institutional surgical database was queried for all surgical procedures during the study time period in patients with conotruncal anomalies, defined as tetralogy of Fallot, d-transposition of the great arteries, truncus arteriosus, double-outlet right ventricle, l-transposition of the great arteries, anterior malalignment (Eisenmenger type) VSD, posterior malalignment VSD, double-outlet left ventricle, and aorta arising from the right ventricle with pulmonary atresia. Patients were included if they were 0 to 18 years of age, underwent biventricular repair that included patch closure of a VSD from the left ventricle to a great artery (ie, VSD baffle to the aortic valve or a truncal valve or VSD baffle to the pulmonary valve with an arterial switch operation or Damus-Kaye-Stansel procedure), and had a postoperative transthoracic echocardiogram (TTE) that evaluated for residual VSD (adequate sweeps of the interventricular septum in 2 dimensions and color Doppler in ≥2 views).
The images of all first postoperative TTEs were reviewed (by M.S.C.) for type of residual VSD. Intramural VSDs were defined as communications located anterior to the VSD patch between the great artery and the right ventricular trabeculations. To meet the definition, the VSD patch had to be seen attached to the right ventricular trabeculations rather than anchored to the right ventricular free wall adjacent to the annulus of the semilunar valve (Figure 2). Residual nonintramural VSDs were defined as peripatch VSDs (defect associated with the VSD patch, with appropriate patch placement adjacent to the annulus of the semilunar valve) or muscular VSDs (within the muscular septum). Patients who had both an intramural VSD and a nonintramural VSD were classified in the intramural VSD group. VSDs were measured and categorized as ≤2 or >2 mm because studies have reported that most VSDs ≤2 mm close spontaneously or typically do not require reintervention.2,4 Additionally, the most recent echocardiogram for all patients with residual VSD who did not require reintervention was reviewed for presence and size of a residual VSD on follow-up.
Data on hospital course were abstracted from inpatient and outpatient medical records. Parameters assessed included baseline demographics and potential clinical risk factors for postoperative morbidity and mortality5–9 (Table I in the online-only Data Supplement). The Society of Thoracic Surgeons–European Association for Cardio-Thoracic Surgery (STS-EACTS) mortality categories10 and operative times were abstracted from the institutional surgical database. Significant comorbidity was defined as a major medical condition requiring operative or medical treatment. Prematurity was defined as gestational age <37 weeks.
The primary outcome event was a composite of mortality, ECMO use, or reintervention on the residual VSD via a surgical or catheter procedure. A composite outcome was used to have a large enough number of outcomes to allow adjustment for potential confounders of the primary association between residual VSD and outcome. The secondary end point was PLOS. Given that some subjects such as premature infants had long hospitalizations before their surgery, PLOS was selected as more relevant to the effect of the operation on hospitalization than total hospital length of stay. Primary outcome events were ascertained for 30 days after operation or until hospital discharge if the PLOS was >30 days.
To evaluate the interrater reliability for identification of intramural VSDs, another experienced echocardiography reader (S.N.) reviewed 10% of TTEs, and the interrater agreement was calculated by the κ statistic.
Descriptive statistics (expressed as count [percentage] or median [interquartile range (IQR)]) were used. The χ2 test and Kruskal-Wallis equality-of-populations rank test were used to evaluate categorical and continuous variables between patients with residual intramural VSD (including those with a residual nonintramural VSD also), patients with only residual nonintramural VSD (peripatch or muscular defects), and patients with no residual VSD. Continuous variables were converted to dichotomous variables on the basis of standards from previous literature and from review of the distribution of our data. The decision was made to analyze the STS-EACTS mortality category as a continuous variable because the mortality rate proceeded in a fairly continuous fashion with an ≈2-fold increase in mortality rate with each incremental increase in STS-EACTS category.10 Bivariable analysis was performed to identify risk factors for the primary composite outcome and for the logarithm of the secondary outcome of PLOS with logistic and linear regression. Multivariable regression models were then built to identify factors independently associated with outcome event and the logarithm of PLOS. Covariates with a value of P<0.2 on bivariate analysis were considered for inclusion in the final multivariable model and retained if P<0.05 or if there was evidence for significant confounding or effect modification. When multiple covariates were found to be highly collinear, the variable that produced the model with the lowest Akaike Information Criterion score (posttest goodness-of-fit measure) was selected. Significant P values were determined a priori as <0.05. All statistical analyses were performed with STATA software (version 12.1, StataCorp, College Station, TX).
Review of the surgical database yielded 903 surgical procedures in patients with conotruncal defects over the 7-year study period. Of these, 462 were biventricular repairs of conotruncal defect involving baffle closure of a VSD from the left ventricle to a great artery. Nineteen patients were excluded because they did not have postoperative TTE to adequately evaluate for residual VSD, and 1 patient who was >18 years of age was excluded, leaving 442 patients who met the inclusion criteria for analysis.
Postoperative TTE was performed at a median of 4 days (IQR, 2–7 days) after surgery. In the cohort, 256 patients (58%) had at least 1 residual VSD, and 19 of the 256 patients (7%) had 2 types of residual VSD. With regard to residual VSD type, 49 subjects (11%) had intramural VSDs, 207 subjects (47%) had only nonintramural VSDs (peripatch or muscular defects), and 186 subjects (42%) had no residual VSD.
Characteristics of the cohort based on type of residual VSD are summarized in Table 1. There were differences in age at operation across residual VSD types, with those with nonintramural VSD being the youngest (64 days; IQR, 6–120 days) and those with no residual VSD being the oldest (93 days; IQR, 10–139 days) at the time of operation. Residual intramural VSDs were seen after repair of all types of conotruncal defects, with a disproportionate number occurring in the less common anomalies such as anterior malalignment (Eisenmenger type) VSD and aorta arising from the right ventricle with pulmonary atresia. The occurrence of an intramural VSD did not vary by sex or type of surgery performed. The vast majority (231 of 256 [90%]) of subjects with residual VSD had defects <2 mm in diameter. Intramural VSDs were more likely to be larger (>2 mm in diameter) than other types of residual VSDs (19 of 49 [39%] versus 6 of 207 [3%]; P<0.0001).
Primary Outcome Events
The composite outcome event (death, ECMO use, or VSD reintervention) occurred more frequently in subjects with intramural VSDs compared with those with only nonintramural VSDs or no residual VSD (14 of 49 [29%] versus 15 of 207 [7%] versus 6 of 186 [3%]; P<0.0001; Table 2). Additionally, all the individual component events of the composite outcome occurred more frequently in subjects with intramural VSD compared with the other subjects.
Bivariable and multivariable models of potential risk factors for composite outcome event were created (Table 3). In the unadjusted analysis, subjects with a residual intramural VSD and a nonintramural VSD were more likely to have an outcome event compared with those with no residual VSD (odds ratio, 12.0; 95% confidence interval, 6.3–33.4; P<0.0001; and odds ratio, 2.3; 95% confidence interval, 0.89–6.2; P=0.09). A multivariable model demonstrated that the presence of an intramural VSD (odds ratio, 4.3; 95% confidence interval, 1.2–15.6; P=0.03) was a significant independent risk factor for the outcome event after controlling for VSD size, additional congenital abnormality or comorbidity, STS-EACTS mortality category, and birth weight.
There were 7 surgical and 3 catheter-based reinterventions on a total of 9 of the 49 patients (18%) with residual intramural VSDs. The VSD size was >2 mm on the first postoperative TTE for 7 of the 9 patients (78%) who subsequently underwent reintervention and 12 of the 40 patients (30%) who did not (P=0.008). Catheterization was performed postoperatively on 8 of the children who had reintervention and 13 of those who did not have reintervention. Children who underwent reintervention had a higher ratio of pulmonary to systemic blood flow (2.1 [IQR, 1.6–2.9] versus 1.3 [IQR, 1.0–1.6]; P=0.03). Additionally, children who underwent reintervention had a longer time on inotropic agents (10 days [IQR, 7–11 days] versus 2 days [IQR, 0–5 days]; P=0.0005) and on ventilator support (30 days [IQR, 14–47 days] versus 4 days [IQR, 0–11 days]; P=0.001) during their hospital stay.
PLOS and Hospital Course
The PLOS was significantly longer in subjects with residual intramural VSDs compared with those with residual nonintramural VSDs or no residual VSD (20 days [IQR, 11–42 days] versus 7 days [IQR, 5–14 days] versus 6 days [IQR, 4–11 days]; P=0.0001). Bivariable and multivariable analyses were performed to evaluate the association of potential risk factors with PLOS (Table 4). The multivariable model demonstrated that presence of intramural residual VSD remained significantly associated with longer PLOS after controlling for VSD size, STS-EACTS mortality category, birth weight, and the presence of a genetic syndrome.
In addition to longer PLOS, subjects with residual intramural VSD had more complicated hospital courses (Table 2). They were more likely to have cardiac arrest or arrhythmia requiring therapy. They also had more days requiring intubation, chest tubes, inotropic agents, and milrinone therapy.
Follow-Up of Residual Defects
Of the 237 subjects with a residual VSD on postoperative TTE who did not have early surgical or catheter reintervention, 183 had a follow-up TTE performed a median of 1.6 years (IQR, 0.5–4.0 years) after the operation. On follow-up TTE, a residual VSD was present in 10 of 33 subject (30%) with previously visualized intramural VSDs and 43 of 150 (29%) with nonintramural VSDs (P=0.9). No subjects in the intramural VSD group and 2 subjects in the nonintramural VSD group had VSDs >2 mm on follow-up echocardiogram (P=0.5). During follow-up, 1 subject underwent reoperation for VSD patch dehiscence, and 6 subjects had small residual VSDs closed as part of another procedure (ie, right ventricle to pulmonary artery conduit replacement or right ventricular outflow tract pseudoaneurysm resection).
In the identification of intramural VSDs based on postoperative TTE, there was high interrater agreement, with a κ statistic of 0.884 (95% confidence interval, 0.662–1.000).
To the best of our knowledge, this study represents the first comprehensive evaluation of the prevalence, risk factors, and outcomes in patients with conotruncal malformations who have residual intramural VSDs after surgery. It is likely that these defects have generally not been recognized as a clinical entity distinct from other residual VSDs in conotruncal repairs.
In this study, we evaluated 442 patients with conotruncal defects undergoing repair. Operations reflected the modern surgical strategy at our institution, with the majority of surgical repairs occurring in the first few months of life. Our rate of residual VSDs detected by postoperative TTE was 68%; this is similar to a prior study reporting a rate of 52%11 and higher than another study with a rate of 38%.12 The vast majority of subjects (90%) in our study with residual VSDs had small defects (<2 mm).
In our cohort, intramural VSDs occurred in 11% of children after repair of conotruncal anomalies and made up 19% of all residual VSDs. There was no association between early age at repair and intramural VSD, suggesting that these defects are not occurring because of small patient size.
Case reports have described intramural VSDs after surgery for d-transposition of the great arteries, tetralogy of Fallot, double-outlet right ventricle, and truncus arteriosus,1–3 but whether they occur in other types of conotruncal defects has not been previously reported. We found that intramural VSDs occurred in subjects after biventricular repair of any type of conotruncal defect that involved baffle closure of the VSD from the left ventricle to a great vessel. Although the majority (33 of 49 [67%]) of intramural VSDs were seen in patients with tetralogy of Fallot (the most common conotruncal defect), the occurrence rate of intramural VSDs was higher in patients with less common forms of conotruncal defects such as double-outlet left ventricle or aorta arising from the right ventricle with pulmonary atresia. We hypothesize that this increased occurrence rate may be attributable to the challenge of optimal VSD patch placement in these anatomically complex conotruncal defects. Although we did not identify an association between occurrence of intramural VSD and type of operation performed, we did observe that the rate of intramural VSDs was higher in complex operations such as the combined atrial switch and Rastelli procedures.
We found that intramural VSDs were more likely to be larger than nonintramural VSDs, which may in part explain their associated morbidity and mortality. However, intramural VSDs were still associated with worse outcomes even after adjustment for residual VSD size, suggesting that other characteristics of these defects may affect surgical outcome. We surmise that some of the intramural VSDs that were small on the first postoperative TTE may have subsequently become larger. They may also be larger than they appear by TTE because of their complex serpiginous course; thus, TTE may underestimate their size. From an anatomic standpoint, we believe these VSDs may enlarge over time because the defects are not between stitches of a patch but rather through right ventricular free wall trabeculations. There may be more impetus for flow across an intramural VSD as the patch pulls further away from the right ventricular free wall. Preminger et al1 hypothesized that intramural VSDs can initially be small and enlarge postoperatively as the hypertrophy of the decompressed right ventricle resolves. This finding has also been supported by Yang et al,2 who reported that 4 subjects with no or small VSDs seen on intraoperative transesophageal echocardiogram were subsequently found to have large intramural VSDs on TTE that eventually required reoperation. Belli et al3 subsequently suggested a transaortic surgical approach for closure of intramural VSDs because of their unusual location and the difficulty in surgical visualization of these defects; they reported successful reoperations in 3 cases.
The outcome of patients with intramural VSDs was previously unknown. Intramural VSDs were associated with significant morbidity and mortality in the initial case series reported by Preminger et al,1 in which all 8 patients described required multiple reoperations and 3 patients died. Four subjects with an intramural VSD in another series2 required surgical reoperation to close the VSD. However, it was unclear if these cases represented all subjects with intramural VSDs or if there was a reporting bias of the most severe defects. Indeed, Belli et al3 were the first to note that not all intramural VSDs were clinically significant. Three of the 5 subjects they reported with intramural VSD required reoperation, whereas the other 2 patients had trivial, insignificant intramural VSDs seen incidentally during angiography performed for outflow tract obstruction.
By systematically reviewing all patients at our institution who underwent conotruncal repair, we observed an association between intramural VSDs and postoperative morbidity and mortality. Subjects with intramural VSDs were more likely to have postoperative mortality, to require ECMO support, and to require reintervention compared with subjects with nonintramural residual VSDs or no residual VSD. This difference persisted after adjustment for known risk factors for postoperative morbidity and mortality. Moreover, although the PLOS for our total cohort was similar to other reports for patients after repair of conotruncal defects,6,13 we found that those with intramural VSDs had a significantly longer PLOS compared to those with a nonintramural VSD or no VSD after surgery. This difference persisted after correction for potential confounders. Overall, the hospital course of subjects with intramural VSDs was more complicated, with more cardiac arrests, arrhythmia, and days of mechanical ventilation and vasopressive support. Although the majority of children with intramural VSDs still did not require reintervention, these children may benefit from VSD reintervention if the defect is large by TTE, if there is a large shunt by cardiac catheterization, or if they are unable to be weaned from respiratory or circulatory support.
The mechanism by which intramural VSDs cause increased morbidity and mortality is not fully understood. It is likely that patients with intramural VSDs have higher morbidity because these VSDs become larger and more hemodynamically significant early in the postoperative period. It is also possible that these VSDs are more difficult to detect accurately on intraoperative transesophageal echocardiography and thus may be underappreciated until the postoperative TTE. Patients with conotruncal defects may poorly tolerate a significant residual VSD in the postoperative period because of preferential shunting across the VSD, resulting in low cardiac output syndrome. In addition, the hearts of children with tetralogy of Fallot or double-outlet right ventricle with pulmonary stenosis have not previously been exposed to a volume load. This sudden volume load may lead to ventricular dysfunction and need for ECMO support, as well as other intensive care morbidities such as longer ventilation time and the development of pleural and pericardial effusions.
Despite the association of intramural VSDs with poor postoperative outcome, it is important to note that the majority of patients with these defects do not require reintervention. In our study, 71% of patients with an intramural VSD did not have an outcome event. We hypothesize that there is an early postoperative period of vulnerability during which these intramural VSDs may become hemodynamically significant. However, if the intramural VSD does not substantially enlarge during this time period, then the outcomes can be similar to the favorable results seen with nonintramural residual VSDs. This is supported by our finding that only 30% of patients with intramural VSDs on the postoperative TTE who did not require reintervention had a residual VSD on most recent follow-up TTE, which was a rate similar to the rate of closure seen in patients with nonintramural VSDs (34%). Similarly, ≈30% of tetralogy of Fallot patients with VSD on early postoperative TTE are known to have residual VSD at follow-up.4
There are several limitations to this study. This was a single-center study that reflects the population at 1 large referral hospital. It was a retrospective review of acquired TTE images, so it is possible that residual VSDs were not noted as a result of a lack of adequate image acquisition. This would cause a bias in underreporting of the prevalence of residual VSDs. Our standard hospital TTE protocol includes sweeps to examine the ventricular septum in multiple views, which should have adequately identified the majority of these VSDs. We also excluded subjects who did not have adequate postoperative TTE; some of these subjects may not have undergone postoperative imaging because they were unwell. However, the number of subjects excluded was small (n=19 [4%]), and any bias would be unlikely to change our results significantly. The diagnosis of intramural and nonintramural VSD was dependent on the TTE read by the study authors. We believe the criteria for diagnosing intramural VSDs were standardized in our echocardiography laboratory, and this was reflected in our high interrater agreement. Furthermore, because of the relatively small number of composite outcome events, there is a possibility of overfitting the final multivariable models for primary outcome event or length of stay. However, the magnitude of our odds ratios and the width of the 95% confidence intervals did not change substantially for any of the covariates going from bivariable to multivariable testing, suggesting that these models are valid. Additionally, logistic regression has been shown in simulation studies to be valid at event-to-variable ratios comparable to what we have used.14 Finally, although attempts were made to adjust for confounding variables in evaluating the association of residual VSDs to the outcome events, it is possible that there are additional confounding events that were not taken into account.
Intramural VSDs occur after repair of conotruncal anomalies and are a clinical entity distinct from peripatch or muscular residual VSDs. In patients after conotruncal repair, intramural VSDs are associated with higher postoperative morbidity and mortality, more frequent reintervention, and longer PLOS. Our findings suggest that early recognition of these lesions may identify a population at risk for postoperative events. Increased awareness of intramural VSDs and focus on surgical strategies to prevent their occurrence may improve overall outcome for patients with conotruncal anomalies who undergo biventricular repair. Further prospective work is needed to confirm these findings and to characterize the intramural VSD prevalence and patient outcomes in a multicenter experience.
Source of Funding
Dr Patel is supported by a grant from the National Institutes of Health (grant T32HL007915).
The online-only Data Supplement is available with this article at http://circ.ahajournals.org/lookup/suppl/doi:10.1161/CIRCULATIONAHA.115.017038/-/DC1.
- Received April 29, 2015.
- Accepted July 30, 2015.
- © 2015 American Heart Association, Inc.
- Preminger TJ,
- Sanders SP,
- van der Velde ME,
- Castañeda AR,
- Lock JE
- Yang SG,
- Novello R,
- Nicolson S,
- Steven J,
- Gaynor JW,
- Spray TL,
- Rychik J
- Kirsch RE,
- Glatz AC,
- Gaynor JW,
- Nicolson SC,
- Spray TL,
- Wernovsky G,
- Bird GL
- O’Brien SM,
- Clarke DR,
- Jacobs JP,
- Jacobs ML,
- Lacour-Gayet FG,
- Pizarro C,
- Welke KF,
- Maruszewski B,
- Tobota Z,
- Miller WJ,
- Hamilton L,
- Peterson ED,
- Mavroudis C,
- Edwards FH
- Cepeda MS,
- Boston R,
- Farrar JT,
- Strom BL
Intramural ventricular septal defect (VSD) is a type of residual defect that can occur after biventricular repair of conotruncal defects such as tetralogy of Fallot, transposition of the great arteries, and double-outlet right ventricle. The defect was first described in a case series of 8 patients >20 years ago. In this previous series, intramural VSDs were associated with considerable morbidity and mortality, including multiple unsuccessful reoperations and 3 deaths. Since that time, intramural VSDs have not been well studied or characterized. To the best of our knowledge, this study represents the first comprehensive evaluation of the prevalence, risk factors, and outcomes of residual intramural VSDs. We evaluated 442 children with repaired conotruncal defects and found that the presence of an intramural VSD, as identified by postoperative transthoracic echocardiogram, was associated with early mortality, extracorporeal membrane oxygenation use, and need for subsequent catheter or surgical VSD closure. The presence of an intramural VSD was also associated with a longer postoperative length of stay. Our study offers compelling evidence that the residual intramural VSD is a distinct clinical entity that is associated with worse postoperative outcome compared with other types of residual VSD. Recognition of this lesion may identify a population of children at risk for postoperative events who may benefit from close follow-up. Additionally, given the morbidity of intramural VSDs, increased awareness to prevent these lesions and to identify them early may improve overall outcome for patients with conotruncal anomalies who undergo biventricular repair.