Background
A Pediatric Heart Network trial compared outcomes in infants with single right ventricle anomalies undergoing Norwood procedures randomized to modified Blalock-Taussig shunt (MBTS) or right ventricle–to–pulmonary artery shunt (RVPAS). Doppler patterns in the neo-aorta and RVPAS may characterize physiologic changes after staged palliations that affect outcomes and right ventricular (RV) function.
Methods
Neo-aortic cardiac index (CI), retrograde fraction (RF) in the descending aorta and RVPAS conduit, RVPAS/neo-aortic systolic ejection time ratio, and systolic/diastolic (S/D) ratio were measured early after Norwood, before stage II palliation, and at 14 months. These parameters were compared with transplantation-free survival, length of hospital stay, and RV functional indices.
Results
In 529 subjects (mean follow-up period, 3.0 ± 2.1 years), neo-aortic CI and descending aortic RF were significantly higher in the MBTS cohort after Norwood. The RVPAS RF averaged <25% at both interstage intervals. Higher pre–stage II descending aortic RF was correlated with lower RV ejection fraction ( R = −0.24; P = .032) at 14 months for the MBTS cohort. Higher post-Norwood CI (5.6 vs 4.4 L/min/m 2 , P = .04) and lower S/D ratio (1.40 vs 1.68, P = .01) were correlated with better interstage transplantation-free survival for the RVPAS cohort. No other Doppler flow patterns were correlated with outcomes.
Conclusions
After the Norwood procedure, infants tolerated significant descending aortic RF (MBTS) and conduit RF (RVPAS), with little correlation with clinical outcomes or RV function. Neo-aortic CI, ejection time, and S/D ratios also had limited correlations with outcomes or RV function, but higher post-Norwood neo-aortic CI and lower S/D ratio were correlated with better interstage survival in those with RVPAS.
Initial surgical palliation for hypoplastic left heart syndrome (HLHS) and other single right ventricular (RV) anatomic variants has evolved to two different strategies that vary on the basis of the source of pulmonary blood flow: the modified Blalock-Taussig shunt (MBTS) or the right ventricle–to–pulmonary artery shunt (RVPAS). These surgical strategies result in different physiologic states that affect flow patterns in the reconstructed aorta (neo-aorta). In a patient with HLHS and an MBTS, all RV cardiac output is exclusively ejected into the neo-aorta before being distributed to the systemic and pulmonary vascular beds; the aortopulmonary shunt allows diastolic “steal” of systemic blood into the pulmonary vascular bed. This is in contrast to a patient with HLHS and an RVPAS, in whom RV cardiac output is distributed directly to both the systemic vascular bed (through the neo-aorta) and the pulmonary vascular bed (through the RVPAS) during systole. No diastolic steal is present, but an additional volume load is placed on the right ventricle as a result of diastolic retrograde flow from the pulmonary artery back into the right ventricle through the nonvalved conduit. Changes in RV systolic and diastolic function, altered systemic and pulmonary vascular resistances, and anatomic resistance to flow into both shunts can affect these neo-aortic and RVPAS flow patterns and are identifiable by Doppler interrogation using echocardiography after initial staged palliation. Specifically, these patterns can estimate neo-aortic cardiac output, antegrade and retrograde flow profiles in the RVPAS and descending aorta (to quantify retrograde fractions through the shunt and neo-aortic arch), and systolic ejection times into the RVPAS and neoaorta (which should reflect relative resistance to flow into the two vascular beds).
Currently, there is no single measure that defines RV function by echocardiography. Two-dimensional assessment of RV volumes and ejection fraction is difficult because of the complex geometry of the chamber. The systolic-to-diastolic duration ratio, as calculated from the tricuspid regurgitation spectral Doppler signal, has been shown to be an indicator of global RV function in children with HLHS, with an increasing ratio correlated with poorer RV function. The calculation of the systolic-to-diastolic duration ratio is made by measuring the systolic duration (from onset to cessation of regurgitant flow from the tricuspid insufficiency jet) and diastolic duration (the time when there is no tricuspid insufficiency flow signal). These intervals can also be calculated from spectral Doppler flow patterns in the RVPAS (measuring systolic antegrade and diastolic retrograde time intervals) in infants with HLHS who have undergone the Sano modification for stage I palliation. This new ratio is attractive because it would be available and easily obtained by echocardiography in every infant with an RVPAS; this is in contrast to calculation of the ratio from tricuspid regurgitation, for which a measureable Doppler signal is available in only about 80% of infants with HLHS.
The Pediatric Heart Network Single Ventricle Reconstruction (SVR) trial compared outcomes in 549 infants undergoing Norwood procedures randomized to either MBTS or RVPAS at 15 North American centers. As part of the SVR trial, two-dimensional and Doppler echocardiographic studies were evaluated at a core laboratory. Echocardiographic indices were measured with the purpose of assessing the effect of MBTS versus RVPAS at four stages during the trial. Correlations of neo-aortic and RVPAS flow patterns with clinical outcomes in the SVR cohort have not been previously examined. In the present study, we analyzed Doppler indices of neo-aortic and RVPAS flow to more fully characterize the SVR cohort. We specifically wanted to compare these Doppler flow patterns with rates of transplantation-free survival, length of hospital stay, indices of RV size and systolic/global function, and degree of tricuspid regurgitation before and after the staged surgical palliations performed during the first 14 months of life.
Methods
Study Design
The SVR study design , primary outcome (incidence of death or cardiac transplantation at 12 months after randomization), and secondary outcomes (morbidity during hospitalizations for the Norwood and stage II procedures, unintended cardiovascular interventions and rate of serious adverse events through 12 months, angiographically derived pulmonary artery size before the stage II procedure), and risk factors for mortality and cardiac transplantantion have been previously published. Secondary echocardiographic markers of outcomes, including indices of RV function, cardiac and vascular dimensions, valve annular dimensions and function, and neoaortic flow patterns in survivors of the Norwood procedure, have been previously summarized and were shown to be similar for subjects with MBTS and RVPAS by 14 months of age.
Echocardiographic Analysis
An echocardiography core laboratory at the Medical College of Wisconsin reviewed two-dimensional and Doppler echocardiograms performed at each clinical center to compare indices between shunt groups at four predesignated time intervals during the study: (1) baseline (before the Norwood procedure) at a mean of 2.1 ± 3.4 days of age, (2) after Norwood (either at the time of discharge or at approximately 30 days of age if still hospitalized) at a mean of 22.1 ± 12.6 days of age, (3) before stage II (during the preoperative evaluation for the stage II procedure) at a mean of 4.7 ± 1.5 months of age, and (4) 14 months of age (end of study visit) at a mean of 14.3 ± 1.2 months. Core lab procedures for image analysis and data management have been previously described.
Five Doppler indices were the focus of this study:
- •
Neo-aortic cardiac index, calculated as stroke volume across the neo-aortic valve: [(neo-aortic velocity-time integral) × (neo-aortic valve area)] × heart rate (beats/min) indexed to body surface area (m 2 ).
- •
Descending aortic retrograde fraction, calculated as the percentage of retrograde diastolic flow in the descending aorta, using pulsed-wave Doppler from the suprasternal notch window to measure velocity-time integrals of antegrade systolic and retrograde diastolic flow in the descending aorta: (diastolic velocity-time integral/systolic velocity time integral) × 100.
- •
RVPAS retrograde fraction, calculated as the percentage of retrograde diastolic flow in the RVPAS, using pulsed-wave Doppler to measure velocity-time integrals of antegrade systolic and retrograde diastolic flow within the midportion of the shunt: (diastolic velocity-time integral/systolic velocity-time integral) × 100.
- •
Ratio of RVPAS to neo-aortic ejection times, calculated as the ratio of the durations of systolic flow from the Doppler jets at the midportion of the shunt and at the neo-aortic annulus: RVPAS systolic ejection time/neo-aortic systolic ejection time.
- •
Systolic-to-diastolic duration ratio in subjects with RVPAS, calculated as the ratio of the systolic duration (from onset to cessation of antegrade flow within the shunt) to diastolic duration (from cessation to onset of antegrade flow within the shunt) obtained from pulsed Doppler tracings in the midportion of the RVPAS ( Figure 1 ): systolic duration/diastolic duration.
Figure 1
Systolic and diastolic time intervals obtained from flow signals in the mid-RVPAS with pulsed-wave Doppler echocardiography in an infant with HLHS after the Norwood procedure. The systolic duration is defined as the time from onset to cessation of antegrade flow (the flow signal below the baseline) and the diastolic duration as the time from cessation to onset of antegrade flow within the shunt (see arrows ). PA , Pulmonary artery; RV , right ventricle.
Outcomes to compare with these Doppler measures included the following:
- 1.
Transplantation-free survival for the following intervals:
- a.
Interstage (Norwood discharge to stage II admission)
- b.
Baseline and post-Norwood echocardiographic studies to stage II admission
- c.
Pre–stage II echocardiographic study to stage II discharge
- d.
Stage II discharge to latest follow-up
- e.
Long-term (from the time of each echocardiographic study to latest follow-up)
- a.
- 2.
Length of intensive care unit stay after Norwood (for the baseline and post-Norwood echocardiographic studies); length of intensive care unit stay after stage II (for the pre–stage II echocardiographic study)
- 3.
Length of hospital stay after Norwood (for the baseline and post-Norwood echocardiographic studies); length of hospital stay after stage II (for the pre–stage II echocardiographic study)
- 4.
Indexed RV end-diastolic and end-systolic volumes, RV ejection fraction, and RV fractional area change (calculated as previously described ) from each echocardiographic study for the RVPAS and MBTS subgroups
- 5.
Severity of tricuspid regurgitation, graded by color Doppler jet width, creating two groups defined as those with less than moderate regurgitation (jet width < 2.5 mm) and those with moderate or greater regurgitation (jet width ≥ 2.5 mm) from each echocardiographic study for the RVPAS and MBTS subgroups
- 6.
Myocardial performance index (MPI), calculated two ways; from blood flow Doppler and annular Doppler tissue imaging measures as previously described, from each echocardiographic study for the RVPAS and MBTS subgroups
Statistical Analysis
Summary descriptive statistics of echocardiographic indices are presented (by shunt type in place at the end of the Norwood operation) at each echocardiographic interval. Hazard ratios and P values were calculated from a Cox proportional-hazards regression predicting time to death or transplantation for each time interval as a function of each Doppler variable. For the six continuous echocardiographic outcomes (RV end-diastolic volume indexed to body surface area, RV end-systolic volume indexed to body surface area, RV ejection fraction, RV area change expressed as a percentage, and MPI using both the pulsed Doppler and Doppler tissue imaging calculations), separate univariate regressions were performed for each combination of the Doppler measure as a predictor of the echocardiographic outcome. For the one dichotomous outcome (at least moderate tricuspid valve regurgitation), separate logistic regressions were performed predicting at least moderate tricuspid valve regurgitation as a function of each of the Doppler measures. Correlations and regression results with P values < .05 were considered significant. All analyses were conducted using SAS version 9.2 (SAS Institute, Inc., Cary, NC).
Results
There were 549 SVR trial subjects; as previously described, five additional subjects who did not undergo the Norwood procedure and one subject who withdrew from the trial in week 1 were excluded. A total of 268 infants undergoing Norwood procedures received MBTS, and 281 infants received RVPAS; all were included in this study cohort except for 17 subjects who had both shunts in place after the initial Norwood procedure or who crossed over to a different shunt after the initial Norwood procedure. In addition, three subjects underwent biventricular repair after the initial Norwood procedure and were also excluded from these analyses.
All available data from the remaining 529 SVR subjects’ baseline, post-Norwood, pre–stage II, and 14-month echocardiograms were included in the study cohort. Fifteen subjects underwent heart transplantation before their 14-month visits, so only echocardiographic data collected before the date of heart transplantation were included in these analyses. Mean follow-up for the entire cohort from the time of initial pre-Norwood echocardiography was 3.0 ± 2.1 years (median, 3.9 years). Table 1 summarizes the number of protocol echocardiograms obtained at each stage throughout the trial (the primary reasons for failure to obtain an echocardiogram being death or transplantation) and the number of echocardiograms that had at least one Doppler measure available for analysis. Table 2 summarizes the mean values for each Doppler measure at each time interval for both shunt groups, and Tables 3 and 4 summarize the correlation between the Doppler measures and transplantation-free survival during the different intervals for each shunt group. A brief summary of the findings for each Doppler measure as it relates to RV function and clinical outcomes is described below.
| Visit | Echocardiography | Doppler assessment |
|---|---|---|
| Pre-Norwood | 529 | 315 |
| Post-Norwood | 468 | 433 |
| Pre–Stage II | 379 | 356 |
| Variable | MBTS | RVPAS | P |
|---|---|---|---|
| Pre-Norwood | |||
| Neo-aortic cardiac index (L/min/m 2 ) | 9.37 ± 3.69 ( n = 166) | 8.67 ± 3.25 ( n = 148) | .07 |
| Post-Norwood | |||
| Neo-aortic cardiac index (L/min/m 2 ) | 8.10 ± 2.67 ( n = 198) | 4.43 ± 2.04 ( n = 190) | <.001 |
| Descending aortic retrograde fraction | 0.45 ± 0.16 ( n = 195) | 0.04 ± 0.12 ( n = 187) | <.001 |
| RVPAS retrograde fraction | NA | 0.23 ± 0.08 ( n = 161) | — |
| Ratio of RVPAS to neo-aortic ejection time | NA | 1.49 ± 0.20 ( n = 155) | — |
| Systolic/diastolic duration ratio | NA | 1.41 ± 0.34 ( n = 170) | — |
| Pre–stage II | |||
| Neo-aortic cardiac index (L/min/m 2 ) | 9.42 ± 3.10 ( n = 145) | 6.15 ± 2.37 ( n = 171) | <.001 |
| Descending aortic retrograde fraction | 0.41 ± 0.19 ( n = 129) | 0.06 ± 0.14 ( n = 158) | <.001 |
| RVPAS retrograde fraction | NA | 0.20 ± 0.07 ( n = 126) | — |
| Ratio of RVPAS to neo-aortic ejection time | NA | 1.43 ± 0.17 ( n = 126) | — |
| Systolic/diastolic duration ratio | NA | 1.64 ± 0.55 ( n = 134) | — |
| Variable | Interstage death/heart transplantation | Death/heart transplantation from date of echocardiography to stage II surgery | Long-term death/heart transplantation from date of echocardiography | |||
|---|---|---|---|---|---|---|
| Yes | No | Yes | No | Yes | No | |
| Pre-Norwood predictors | ||||||
| Neo-aortic cardiac index (L/min/m 2 ) | 9.17 ± 4.32 ( n = 22) | 9.54 ± 3.78 ( n = 112) | 8.93 ± 3.69 ( n = 47) | 9.55 ± 3.69 ( n = 119) | 9.05 ± 3.49 ( n = 58) | 9.55 ± 3.80 ( n = 108) |
| HR | 0.97 | 0.96 | 0.97 | |||
| P | .58 | .28 | .37 | |||
| Post-Norwood predictors | ||||||
| Neo-aortic cardiac index (L/min/m 2 ) | 7.55 ± 2.02 ( n = 39) | 8.24 ± 2.73 ( n = 136) | 7.71 ± 2.40 ( n = 53) | 8.24 ± 2.76 ( n = 145) | 7.91 ± 2.76 ( n = 68) | 8.20 ± 2.63 ( n = 130) |
| HR | 0.91 | 0.93 | 0.96 | |||
| P | .15 | .22 | .36 | |||
| Descend aortic retrograde fraction | 0.43 ± 0.16 ( n = 38) | 0.45 ± 0.14 ( n = 135) | 0.46 ± 0.21 ( n = 50) | 0.45 ± 0.15 ( n = 145) | 0.45 ± 0.19 ( n = 66) | 0.45 ± 0.15 ( n = 129) |
| HR | 0.54 | 1.58 | 1.21 | |||
| P | .59 | .61 | .81 | |||
| Death/heart transplantation from date of echocardiography to stage II discharge | Long-term death/heart transplantation from date of stage II discharge | Long-term death/heart transplantation from date of echocardiography | ||||
|---|---|---|---|---|---|---|
| Yes | No | Yes | No | Yes | No | |
| Pre–stage II predictors | ||||||
| Neo-aortic cardiac index (L/min/m 2 ) | 6.43 ± 1.18 ( n = 5) | 9.53 ± 3.10 ( n = 140) | 9.28 ± 2.16 ( n = 9) | 9.54 ± 3.16 ( n = 131) | 8.26 ± 2.30 ( n = 14) | 9.54 ± 3.16 ( n = 131) |
| HR | 0.58 | 0.97 | 0.86 | |||
| P | .06 | .76 | .12 | |||
| Descending aortic retrograde fraction | 0.49 ± 0.09 ( n = 6) | 0.41 ± 0.19 ( n = 123) | 0.31 ± 0.14 ( n = 10) | 0.41 ± 0.19 ( n = 113) | 0.38 ± 0.15 ( n = 16) | 0.41 ± 0.19 ( n = 113) |
| HR | 13.02 | 0.02 | 0.32 | |||
| P | .21 | .05 | .43 | |||
| Variable | Interstage death/heart transplantation | Death/heart transplantation from date of echocardiography to stage II surgery | Long-term death/heart transplantation from date of echocardiography | |||
|---|---|---|---|---|---|---|
| Yes | No | Yes | No | Yes | No | |
| Pre-Norwood predictors | ||||||
| Neo-aortic cardiac index (L/min/m 2 ) | 11.21 ± 5.50 ( n = 4) | 8.79 ± 3.21 ( n = 120) | 8.00 ± 3.55 ( n = 25) | 8.81 ± 3.18 ( n = 123) | 8.34 ± 3.36 ( n = 44) | 8.81 ± 3.20 ( n = 104) |
| HR | 1.19 | 0.92 | 0.96 | |||
| P | .18 | .24 | .38 | |||
| Post-Norwood predictors | ||||||
| Neo-aortic cardiac index (L/min/m 2 ) | 4.37 ± 1.99 ( n = 12) | 5.58 ± 2.08 ( n = 167) | 4.87 ± 2.38 ( n = 15) | 4.41 ± 2.02 ( n = 173) | 4.21 ± 1.88 ( n = 49) | 4.51 ± 2.09 ( n = 141) |
| HR | 1.22 | 1.08 | 0.95 | |||
| P | .042 | .43 | .52 | |||
| Descending aortic retrograde fraction | 0.00 ± 0.00 ( n = 12) | 0.04 ± 0.12 ( n = 162) | 0.00 ± 0.00 ( n = 16) | 0.04 ± 0.12 ( n = 169) | 0.04 ± 0.11 ( n = 49) | 0.04 ± 0.12 ( n = 138) |
| HR | 0.00 | 0.00 | 1.29 | |||
| P | .99 | .99 | .83 | |||
| RVPAS retrograde fraction | 0.22 ± 0.09 ( n = 9) | 0.23 ± 0.08 ( n = 140) | 0.25 ± 0.09 ( n = 13) | 0.23 ± 0.08 ( n = 146) | 0.24 ± 0.07 ( n = 43) | 0.23 ± 0.08 ( n = 118) |
| HR | 2.38 | 37.22 | 5.24 | |||
| P | .83 | .25 | .36 | |||
| Ratio of RVPAS to neo-aortic ejection time | 1.56 ± 0.12 ( n = 9) | 1.48 ± 0.19 ( n = 135) | 1.58 ± 0.18 ( n = 13) | 1.48 ± 0.19 ( n = 140) | 1.50 ± 0.18 ( n = 42) | 1.49 ± 0.20 ( n = 113) |
| HR | 4.68 | 4.63 | 1.27 | |||
| P | .36 | .25 | .75 | |||
| Systolic/diastolic time ratio | 1.68 ± 0.20 ( n = 9) | 1.40 ± 0.33 ( n = 149) | 1.56 ± 0.31 ( n = 13) | 1.40 ± 0.34 ( n = 155) | 1.45 ± 0.30 ( n = 44) | 1.40 ± 0.35 ( n = 126) |
| HR | 10.22 | 2.90 | 1.42 | |||
| P | .010 | .16 | .41 | |||
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