Abstract
Background:
Despite improvement in the outcome of the Norwood procedure, the prognosis of hypoplastic left heart syndrome (HLHS) remains problematic. The aim of this study was to assess the impact of pre- and perioperative factors and catheterization data on outcomes after the Norwood procedure.
Subjects and Methods:
This case–control study included all patients who underwent the Norwood procedure for HLHS at Fukuoka Children’s Hospital between January 2000 and October 2011. Subjects (n = 66) were divided into two outcome groups: survivors (n = 41) and nonsurvivors (n = 25). First, we compared the pre- and perioperative data. Second, we compared the catheterization data after the Norwood procedure.
Results:
The mean follow-up period was 40 months (range: 1.4–141). Overall, there was a 38% mortality, including early death. The pre- and perioperative data, as well as PaO2 in room air at catheterization, were not significantly different. However, univariate analysis revealed that the incidence of home oxygen therapy to maintain oxygen saturation >80% was significantly higher in the survivors (P < 0.001). The right ventricular ejection fraction was higher in the survivors (48.7% ± 1.9%, mean ± standard error) than in the nonsurvivors (41.4% ± 2.8%, P = 0.041). The severity of tricuspid regurgitation (TR) and the pulmonary blood flow/systemic blood flow ratio were lower in the survivors than in the nonsurvivors. Multivariate logistic regression analysis identified severe TR as the only significant prognostic marker of mortality (P = 0.041).
Conclusions:
The severity of TR was associated with the prognosis of HLHS after the Norwood procedure.
Keywords: Cardiac function, home oxygen therapy, outcomes, pulmonary vascular resistance/hypertension
INTRODUCTION
Hypoplastic left heart syndrome (HLHS) and related anomalies involving a single right ventricle are characterized by hypoplasia of the left heart and aorta, with compromised systemic cardiac output.[1] In Japan, infants with the syndrome generally undergo a three-stage reconstruction procedure culminating in the Fontan circulation because only a limited number of pediatric heart transplantations are performed.[2]
Regardless of the refinements in surgical techniques and perioperative management of the aforementioned three-staged procedures, the prognosis of HLHS after the Norwood procedure remains a problem.[3,4] Interstage ventricular function, or tricuspid regurgitation (TR), would be more important in children with HLHS than the surgical palliation strategy.[5] The aim of this study was to assess the impact of pre- and perioperative factors and catheterization data after the Norwood procedure on outcomes.
SUBJECTS AND METHODS
This was a retrospective, case–control study. The study subjects were all patients diagnosed with HLHS who underwent the Norwood procedure at Fukuoka Children’s Hospital between January 2000 and October 2011. The inclusion criteria were diagnosis of HLHS and suitability for the Norwood procedure, whereas the exclusion criterion was nonsuitability for the Norwood procedure preoperatively based on clinical status, and bilateral pulmonary artery banding was performed [Figure 1]. All patients were Japanese, and the same surgical team performed all operations. In this study, we used antegrade cerebral perfusion for all patients because circulatory arrest could have adverse effects on the brain and multiple organs. All of them received nitric oxide, cardiac stimulants, and diuretics after the Norwood procedure. The medical records, including surgical procedure, angiographic, and echocardiographic data, of all patients were reviewed. First, for comparisons, patients (n = 66) were divided into two groups: survivors (n = 41) and nonsurvivors (n = 25). The follow-up period lasted until July 2012. The requirement for patient consent was waived due to the retrospective nature of the study conducted at a single center. No valvuloplasty was performed in any of the surgeries.
Figure 1.
Flowchart of the number of patients stratified into survivors and nonsurvivors. Patients were assigned to the modified Blalock–Taussig–Thomas shunt (mBTT) or the right ventricular pulmonary artery (RVPA) shunt. They were randomly assigned to one of the above surgical procedures based on certain anatomical factors. mBTT + RVPA shunts were performed to keep oxygenation at the initial operation. MBT: Modified Blalock–Taussig, RVPA: Right ventricular pulmonary artery
Baseline data analysis
Demographic data, including gestational age, sex, birth weight, Apgar scores, anatomic diagnosis at presentation, age at Norwood operation, shunt type, shunt size, aortic clamp time, and duration of cardiopulmonary bypass (CPB), were collected before and peri-Norwood procedure. Shunt size was used to assess the influence on the pulmonary blood flow regulation.[6] The anatomy, size of the ascending aorta, and grade of TR were evaluated by two-dimensional echocardiography. The grade of TR was assessed using color flow Doppler mapping, as a qualitative parameter, ranging from 0 to 3: 0 – none, 1 – mild TR, 2 – moderate TR, and 3 – severe TR.[7]
Analysis of follow-up data
Follow-up data were obtained before the bidirectional Glenn shunt (BDG) to evaluate the incidence of home oxygen therapy (HOT) users and hemodynamic parameters. HOT was started 1 month after the Norwood operation at the latest, and the reason for the introduction of HOT was low arterial oxygen saturation (SpO2) values (mostly SpO2 <80%, measured by pulse oximetry) with considerable fluctuation. Cardiac catheterization was performed routinely before BDG to ascertain the suitability for the procedure. Directly measured arterial oxygen saturation (SaO2), pulmonary/systemic blood flow ratio (Qp/Qs), right ventricular (RV) end-diastolic volume, RV ejection fraction (RVEF), RV end-diastolic pressure, and the degree of TR were evaluated. The degree of TR was assessed using Sellers’ classification: 0 – none, 1 – mild TR, 2 – moderate TR, 3 – moderately severe TR, and 4 – severe TR.[8] The areas of the right and left pulmonary arteries, in mm² per body surface area (m²), were calculated as the pulmonary artery (PA) index.[9] These parameters were measured, while the patient breathed room air.
Statistical analysis
Data were presented as mean ± standard error or median with interquartile ranges for parametric and nonparametric variables, respectively. Differences in variables between the survivors and nonsurvivors were analyzed by univariate analysis: χ2 test, Mann–Whitney U-test, or Student’s t-test, as appropriate. Differences in explanatory variables (RVEF, Qp/Qs, and the severity of TR) were also evaluated. Variables with P < 0.05 were entered into multivariate stepwise logistic regression to determine those associated with prognosis. The data were analyzed using the Statistical Package for the Social Sciences version 21 (SPSS, Chicago, IL). A two-tailed P < 0.05 was considered statistically significant.
RESULTS
Figure 1 shows the outcome of patients who underwent the Norwood procedure. The shunt type was modified Blalock–Taussig–Thomas (mBTT) shunt (3 or 3.5 mm in diameter) in 28 cases and RV pulmonary artery (RVPA) shunt (5 or 6 mm in diameter) in 33 cases. Both mBTT and RVPA shunts were performed in five cases because they could not maintain suitable oxygenation at the initial operation. Four patients of the survivor group had not yet undergone cardiac catheterization, and 12 patients died before cardiac catheterization to determine the suitability for BDG. Table 1 summarizes the baseline demographic data determined before and after the Norwood operation. There were no significant differences in gestational age, sex, birth weight, Apgar scores, anatomic diagnosis at presentation, size of the ascending aorta, severity of TR, age at Norwood operation, shunt type: mBTT or RVPA, aortic clamp time, and duration of CPB between the survivors and the death groups. However, univariate analysis revealed that the incidence of HOT was significantly higher in the survivors (39.0% vs. 4.0%, P < 0.001).
Table 1.
Baseline characteristics
| Characteristics | Survivors (n=41) | Nonsurvivors (n=25) | P |
|---|---|---|---|
| Gender | |||
| Male | 27 | 13 | 0.26¶ |
| Female | 14 | 12 | |
| Gestational age (week) | 38 (38–39)a | 38 (38–9)a | 0.06* |
| Birth weight (g) | 2905 (2724–3160)a | 2900 (2543–3090)a | 0.80* |
| Apgar score at 1 min | 8.0 (8.0–8.5)a | 8.0 (8.0–8.0)a | 0.64* |
| Apgar score at 5 min | 9.0 (8.0–9.0)a | 9.0 (8.0–9.0)a | 0.06* |
| Anatomy, classical/variant | 36/5 | 24/1 | 0.26¶ |
| Obstructed pulmonary venous return | 3 | 2 | 0.9¶ |
| Severe tricuspid valve regurgitation | 0 (0–1.0)a | 0 (0–1.0)a | 0.52* |
| Size of ascending aorta (mm) | 2.5 (2.0–3.2)a | 2.5 (2.3–3.1)a | 0.53* |
| Norwood (day old) | 9.0 (6.0–13.0)a | 9.0 (7.0–11.5)a | 0.80* |
| Shunt type, MBT, n (%) | 16 (40) | 12 (48) | 0.44† |
| RVPA | 22 (53) | 11 (44) | 0.44† |
| MBT + RVPA | 3 (7) | 2 (8) | - |
| Aortic clamp time (min) | 67 (59–82)a | 72 (53–94)a | 0.99* |
| CPB time (min) | 194 (168–236)a | 224 (174–255)a | 0.12* |
| Home oxygen therapy | 16a | 1a | <0.001¶ |
*By Mann–Whitney U-test, ¶Student’s t-test, and †Chi-square test, aThe only significant difference was observed between the presence or absence of home oxygen therapy. Data are presented as the number of patients, mean±SE, or median (IQR). The severity of TR was assessed using color flow Doppler as a qualitative parameter. Indexed shunt size was the ratio of shunt size (mm) and birth weight (kg). IQR: interquartile range, MBT: Modified Blalock-Taussig, RVPA: Right ventricle-pulmonary artery, CPB: Cardiopulmonary bypass, SE: Standard error, TR: Tricuspid regurgitation
The differences in hemodynamic parameters before BDG for both the survivors and nonsurvivors are presented in Table 2. There were no differences in the age at catheterization (131 [111–174] days vs. 109 (108–122) days, P = 0.26). In both the groups, there were no shunt obstructions or interventions for the shunt or pulmonary arteries at catheterization before BDG. Univariate analysis showed that RVEF was significantly higher in survivors than in nonsurvivors (48.7% ± 1.9% vs. 41.4% ± 2.8%, P = 0.041). Conversely, the severity of TR and Qp/Qs ratio was lower in the survivors than the nonsurvivors (0.5 [0–2] vs. 0.5 [0–3], P = 0.033; 0.99 ± 0.08 vs. 1.39 ± 0.12, P = 0.033). Multivariate logistic regression analysis identified the severity of TR as the only risk factor [P = 0.041, Table 3].
Table 2.
Hemodynamic parameters after the Norwood procedure
| Hemodynamic parameters | Survivors (n=37) | Nonsurvivors (n=13) | P |
|---|---|---|---|
| Age at catheterization (days) | 131 (111–174) | 109 (108–122) | 0.26* |
| SaO2 (%) | 79 (76–81) | 78 (74–82) | 0.99* |
| Qp/Qs ratio | 0.99±0.08 | 1.39±0.12 | 0.033¶ |
| RVEDV (% normal) | 152 (128–189) | 158 (131–206) | 0.55* |
| RVEF (%) | 48.7±1.9 | 41.4±2.8 | 0.041¶ |
| RVEDP (mmHg) | 5.0 (4.0–7.0) | 6.5 (5.0–9.0) | 0.34* |
| Severe tricuspid valve regurgitation | 0.5 (0–2.0) | 0.5 (0–3.0) | 0.032* |
| PA index (mm2/BSA) | 192±14 | 206±26 | 0.47¶ |
| PAP (mmHg) | 14.1±1.0 | 15.6±1.9 | 0.36¶ |
| Home oxygen therapy | 16 | 1 | <0.001† |
*By Mann–Whitney U-test, ¶Student’s t-test; and †Chi-square test, Data are mean±SE or median (IQR), The degree of TR was assessed using Sellers’ classification. SaO2: Arterial oxygen saturation, Qp/Qs: Pulmonary to systemic blood flow, RVEDV: Right ventricular end-diastolic volume, RVEF: Right ventricular ejection fraction, RVEDP: Right ventricular end-diastolic pressure, PA index/BSA: Area of the right and left pulmonary artery/body surface area, PAP: Pulmonary artery mean pressure, IQR: Interquartile range, SE: Standard error, TR: Tricuspid regurgitation
Table 3.
Risk factors after the Norwood procedure by multivariate stepwise logistic regression analysis
| Hemodynamic parameters | OR (95%CI) | P |
|---|---|---|
| Severe tricuspid valve regurgitation | 0.328 (0.113–0.956) | 0.041 |
| Qp/Qs ratio | 0.071 (0.004–1.266) | 0.072 |
Qp/Qs: Pulmonary to systemic blood flow ratio, OR: Odds ratio, CI: Confidence interval
The outcome after the onset of HOT was compared between subjects with HOT and those without HOT [Figure 2]. The benefit of HOT after Norwood with respect to survival rate was found (P = 0.014). In this analysis, seven subjects died before catheterization, and three subjects died within 1 month after catheterization. Ten subjects died even after BDG. However, there was no mortality after 72 months. In addition, there were no deaths within 30 days in this study.
Figure 2.
The Kaplan–Meier curves for survival among infants who underwent the Norwood procedure are shown. Home oxygen therapy was initiated 1 month after the Norwood procedure. HOT: Home oxygen therapy
DISCUSSION
This study demonstrated that the presence of TR after the Norwood procedure impacted the outcome, as observed over 11 years in a single center. We reported the real-world data of this difficult substrate with a single ventricle, which is almost at the end of the spectrum. Overall, there was a 38% mortality rate during the interstage period. The single-ventricle reconstruction trial showed a significant survival advantage to RVPA shunts at 1 year.[9] In this study, however, mBTT shunts and RVPA shunts were reasonably distributed between the survivors and nonsurvivors. This finding suggests that the type of shunt used did not affect overall mortality when the Norwood procedure was performed. In addition, the prognosis of patients with HLHS after stage I Norwood procedure is reported to correlate with various factors, including patient-specific anatomical and physiological variables (e.g., prematurity, body weight, age at Norwood operation, size of the ascending aorta, shunt type: mBTT or RVPA, and the severity of TR)[10] as well as various procedure-specific and technical factors (e.g., circulatory arrest time[11,12] and aortic clamp time). Second, according to excellent, detailed, and careful postoperative care, there were no early postoperative deaths, which is why this study included more surviving severe heart failure cases than other studies. It is essential to note that very detailed postoperative care is provided, with special attention paid to patients and their guardians in Japan.
We all know that patients with parallel circulation are better off with a borderline arterial saturation than a high one.[13] In the present study, although the clinical features of patients of the survivors and nonsurvivors at baseline were not different, cardiac catheterization data before BDG suggested RVEF, the severity of TR, Qp/Qs ratio, and HOT were significant in univariate analysis. In the multivariate analysis, we found that the severity of TR was the only risk factor for mortality. These results showed that increased pulmonary flow induced RV dysfunction and deteriorating TR, even if TR was not severe at birth, interstage ventricular function, or TR would be more important in children with HLHS than the surgical palliation strategy to improve outcomes.[5] In fact, RVEF at cardiac catheterization was higher, and SpO2 at leaving the intensive care unit was lower, in comparison of HOT and non-HOT (52.2% vs. 43.9%, P = 0.016; 78.4% vs. 85.5%, P < 0.001).
For the entire group, 17 out of 66 infants were treated with HOT during the study period due to low SpO2 values (<80%) with significant fluctuations. This was an unexpected finding, suggesting that HOT might help improve prognosis. However, in the present study, SaO2 values measured during cardiac catheterization, while breathing room air was not different between the survivors and nonsurvivors before BDG. These data would help improve interstage efficiency, given the numerous cases. However, the retrospective method cannot provide sufficient scientific evidence of a direct link between HOT and mortality. We need to prospectively continue this analysis with a better definition of the need for HOT.
The present study has three limitations. First, this was a retrospective single-center study with inherent limitations related to the incompleteness of data. Actually, we were unable to perform cardiac catheterization immediately before BDG in all cases [Table 1]. Second, although there were no significant differences in pre- and perioperative baseline data between the two groups, the unsophisticated surgical technique and perioperative care in the early period of the study may have affected the outcome. Third, no data were available on Qp/Qs or pulmonary vein saturation changes with oxygen in the subjects after a Norwood operation. Future studies are necessary to assess the effect of HOT on cardiac function and hemodynamics in these subjects. It is known that measures of systolic function, such as RV fractional area change and RVEF, would be overestimated in the presence of significant TR. In addition, it is known that various factors may influence the TroP values beyond myocardial damage during surgery or cardiac interventions.[14,15]
CONCLUSIONS
The severity of TR was associated with the prognosis of HLHS after the Norwood procedure.
Conflicts of interest
There are no conflicts of interest.
Funding Statement
Nil.
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