Mortality and Survival after Norwood Procedure Comparison between Shunt Type in Patients with Hypoplastic Left Heart Syndrome or Its Variants: A Systematic Review and Meta-Analysis Study

Background . In the Norwood procedure, a conduit is performed either from the subclavian artery to the pulmonary artery, Blalock–Taussig shunt (mBTs), or from the right ventricle to the pulmonary artery (RV-PA shunt). Tere are some concerns regarding the two shunts and which one is better according to morbidity and mortality in patients with hypoplastic left heart syndrome or its variants. Methods . We systematically searched PubMed, Web of Science, Scopus, Embase, and Cochrane Library databases from inception to 04/June/2021 to collect articles reporting a comparison of RV-PA shunt and mBTs. Results . Our meta-analysis showed that the mortality rate after 6months, 1, 2, 3, 4, 5, and 6years for the mBTS group was 16.3%, 28.6%, 34.8%, 42.4%, 44.6%, 45.1%, and 39.6%, respectively, and for the RV-PAS, 14.8%, 26.6%, 31%, 40.1%, 36.1%, 37.5%, and 34.0%, respectively. Te mortality rate was signifcantly higher in the mBTs group at 1 and 2years; otherwise, there is no signifcance diferences. Overall complications rate was higher in the mBTs group than in the RV-PAs group (17.8% vs. 8.5%). In contrast, the rate of cardiac complications was higher in the RV-PAS group. Conclusions. Te RV-PA shunt had lower mortality and overall complications rate than mBTshunt at the short-term outcome within the frst two years, but at the long term, there was no diference between the two shunts. On the other hand, the mBT shunt had a lower incidence of cardiac complications at the early stage after the operations. However, some studies are poor due to the difculties in conducting original research in this feld. Terefore, we recommend conducting systematic reviews and original studies to compare these and other therapeutic procedures for these patients.


Introduction
Hypoplastic left heart syndrome (HLHS) and its variants are rare congenital heart defects. Children born with a hypoplastic or absent left ventricle may afect the aorta, aortic valve, or mitral valve. HLHS is fatal without early intervention. Tere are many possible interventions used currently: either a three-stage reconstruction surgery or a heart transplant. Surgical palliation stage 1 was frst described by Norwood et al. in 1983 [1].
In the Norwood procedure, the right ventricle is relied on to pump blood to the body and the lungs. To reduce the deoxygenated blood reaching the right ventricle and to make it pass directly to the lungs, a conduit is performed either from the subclavian artery to the pulmonary artery, Blalock-Taussig Shunt (mBTs), or from the right ventricle to the pulmonary artery (RV-PA shunt).
Te Norwood procedure using the mBT shunt appeared as a good frst procedure to save these patients, but it did not improve the survival much, so the surgeons looked for other better procedures such as RV-PA shunt, and many primary studies were conducted comparing the two procedures to fnd which shunt is better to survival and morbidity. Recently, a hybrid procedure appeared that reduced surgical interventions for HLHS patients in the frst stage instead of Norwood, but studies and diferent surgical experiences between diferent centers are still conficting about its importance.
Tere are still some concerns regarding the two shunts and which one is better. Randomized controlled trials and cohort studies show that RV-PA conduit improves transplant-free survival, but morbidity did not afect the outcome between two shunts [2,3]. A meta-analysis suggested an early survival advantage of RV-PA conduit over the mBTs shunt [4]. In contrast, other studies demonstrated that there is no signifcant diference between the two shunts [5,6] and other studies suggest that the mBTs shunt is better [7].
Accordingly, we decided to conduct a systematic review and meta-analysis to try to answer this question comprehensively according to the medical literature.

Materials and Methods
We conducted our systematic review and meta-analysis following to recommendations of Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 (PRISMA 2020) [8].

Eligibility Criteria.
We include in this systematic review full-text articles reporting a comparison of the RV-PA shunt and mBT shunt in patients with hypoplastic left heart syndrome or its variants who underwent Norwood procedure. We exclude any study that did not mention primary outcome data for both groups. Any study that did not mention mortality, survival, or transplantation was also excluded. Te exclusion criteria also contain review articles, case reports, and case series of less than 10 patients. Book chapters, abstract conferences, articles with no full text or missing information, and studies published in languages other than English or Arabic were also excluded.

Information Sources and Search Strategy.
We systematically searched PubMed, Web of Science, Scopus, Embase, and Cochrane Library databases from inception to 04/June/ 2021 to collect articles reporting a comparison of right ventricle to pulmonary artery conduit and modifed Blalock-Taussig shunt. Te search terms of our search strategy were showed in Appendix A, and the search strategy was modifed to ft each database. No restrictions were applied regarding the date of publication. Te reference sections of the included full-text articles were manually evaluated to fnd more studies eligible for inclusion.

Selection Process.
Te title/abstract and full-text screening processes were conducted by two authors separately, and disagreements were resolved by a third author.

Data Collection
Process. Data were extracted from the eligible studies including frst author's name, year of publication, journal, country, the intervention and control procedures, number of participants in mBTS shunt/Sano shunt groups, gestational age (weeks), birth weight (kg), surgery stage 1 age (days), sex, ascending aorta diameter (mm), surgery weight (kg) at stage 1, aortic atresia, mitral atresia, aortic stenosis, mitral stenosis, noncardiac anomalies, genetic syndrome, cardiopulmonary bypass time (minutes), aortic cross clamp (minutes), and primary outcome that contain mortality or transplantation, and transplant free survival. Secondary outcomes were reoperation, post-Norwood complications, pacemaker placed, proteinlosing enteropathy, and adjudicated cause of death. Data extraction process was performed by one author separately and reviewed by another.

Quality Assessment of the Studies.
For each eligible study, the quality assessment was performed by one investigator and reviewed by another. We assessed the risk of bias in including studies based on Cochrane Collaboration Handbook [9] for RCT studies and the criteria of the Newcastle-Ottawa scale [10] for non-RCT studies. Conficts are resolved through discussion among authors or the involvement of a third author if necessary.

Efect Measures and Synthesis
Methods. Our primary outcomes were analyzed using the random efect model because of the high level of heterogeneity and with the risk ratio (RR) used as the summary statistic in the forest plots. In our analysis, we used the I 2 statistics to estimate the percentage of total variation in each outcome, owing to heterogeneity rather than chance, with values > 50% considered as substantial heterogeneity. Sensitivity analysis was performed. Publication bias was assessed by funnel plots; any extremity result was excluded from the analysis. All statistical analyses were performed using MetaXL software tool. We could not do meta-analysis for our secondary outcomes because they were reported from one or two studies. We calculated the mortality percentage at 6 months, one, two, three, four, fve, and six years by aggregating the number of death events at each time point reported by the included studies divided by the total number of children reported by the included studies.

Identifcation and Selection of Reviews.
We identifed 70 articles accepted in our review, after searching in four databases, doing a manual search, screening title/abstract and full text, and applying our criteria on full-text articles. Tirty-four studies have overlap between patients with other studies, so 36 studies were selected for statistical synthesis including two RCTs and 30 retrospective and four prospective cohort studies. Our PRISMA fow diagram is shown in Figure 1. Te main characteristics of the accepted studies are shown in Table 1.  Table 3.

Characteristic and
A total of 36 studies were assessed as described above. Te only two randomized controlled trials included in our meta-analysis (Single Ventricle Trial and Frommelt et al 2007 study) had a high risk of bias, as selection bias, performance bias, and detection bias were high due to the difculty of randomization and blinding. Twenty-one of the 29 observational studies we included were considered to be at high quality. In contrast, the remaining eight observational studies were judged to be at poor quality because these studies did not report a comparison of surgery stage 1 age, birth weight, or gestational age between the two groups ( Table 4).
All meta-analysis forest plots for this outcome are shown in Figure 2.

Secondary Outcome Results (Complications and Adjudicated Causes of Death).
Overall complications rate was higher in the mBTs group than in the RV-PAs group (17.8% Vs. 8.5%). Te RV-PAs group had less gastrointestinal complications than the mBTs group (3.9% vs. 8.47%). In contrast, the rate of cardiac complications, respiratory complications, neurological complications, infectious complications, and renal complications were higher in the RV-PAs group than in the mBTs group as shown in Table 2. As for the other complications, there was no signifcant diference between the two groups. Furthermore, pacemakers placing rates were slightly higher in the mBTs group (2.5% vs. 2.90%), whereas RV-PAs patients were more likely to develop the protein-losing enteropathy (3.3% vs. 1.59%). Only one study reported the adjudicated causes of death. Mortality from pulmonary, neurological, gastroenterological, and infectious causes was higher in the RV-PAs group, whereas participants in the mBTs group were more likely to die of cardiac or complex/multisystem causes. On the other hand, the death rate from unknown causes was equal between the two groups (1.8% vs. 1.81%), while there was no study reported the death of organ failure cause. Te details of the complications and the adjudicated causes of death data are shown in Table 5.

Discussion
Te Norwood procedure is the frst of the series of three operations which involve performing two diferent systemic to pulmonary shunts to ensure pulmonary blood fow in children with HLHS, either mBT shunt or RV-PA shunt. Te advantage of either shunt over the other has long been a matter of debate, especially with regard to the long-term outcomes. Te results of our meta-analysis indicate the advantage of using the RV-PA shunt to reduce early mortality after S1P and interstage mortality after S1P and before S2P. As for interstage mortality after S2P and before S3P, there was no preference for either of the two shunts over the other. Our meta-analysis provides a look at the mortality after 6 months, 1, 2, 3, 4, 5, and 6 years, in which there was signifcant diference at 1 and 2 years; otherwise, there is no signifcance diference.
Furthermore, mBT shunt was accused of causing higher overall complications rate, and this was confrmed by the results of our study, with varying incidence of these complications in both groups; while the patients who received mBT shunt are more likely to develop gastrointestinal complications, and the patients who received RV-PA shunt are more likely to develop cardiac, respiratory, neurological, infectious, and renal complications, and maybe this is what made some centers use the mBT shunt until now. Because of the small number of studies that reported this outcome, the diferences in complications between the two groups cannot be explained and can be attributed to the diference in medical centers and surgical experience in performing these two procedures.
As for the causes of death, our review found only one paper that reported the various causes of death in both groups, [14] where children with mBT shunt were more likely to die of cardiac or complex/multisystem causes, while children in RV-PA shunt group were more likely to die from other causes.
Te RV-PA shunt is associated with a lower mortality rate in the frst 30 days after S1P or prior to hospital discharge. [4] In addition, the results of the single ventricle trial, which was conducted on 549 children, have shown that the transplantation-free survival at one year was better with the RV-PA shunt. In contrast, the current evidence shows similar results between the two groups after one year of age [3,7]. Although studies have indicated that patients of the   Journal of Cardiac Surgery    Journal of Cardiac Surgery  RV-PA shunt group are relatively less likely to develop complications, caution should be taken against shunt failure, especially during the frst week [6]. Tis is in addition to the serious neurological complications associated with this type of shunt, such as seizure, bleeding, and stroke [7,22]. On the other hand and in the context of constant attempts to develop care for patients with HLHS, the Hybrid procedure has emerged in recent years to be sometimes an alternative to the Norwood procedure [77]. Hybrid procedure shows a good midterm survival in high risk patients [77,78].
Tere are several limitations to the current study. Tese limitations include the lack of high-quality randomized controlled trials due to the nature of the surgical procedure that limits the application of blinding and randomization, there are also some observational studies of poor quality in our review. Te heterogeneity that is sometimes present in some pooling operations, also limits this study. In addition, many of the studies included in the review did not discuss many important details for HLHS patients after the procedure such as the diameter of the artery, pulmonary artery More stars ( * ) indicate higher quality of study. S1, representativeness of exposed cohort; S2, selection of nonexposed cohort; S3, ascertainment of exposure; S4, demonstration that outcome of interest was not present at the start of study; C1, comparability of cohort on basis of design or analysis; O1, assessment of outcome; O2, follow-up long enough for outcomes to occur; O3, adequacy of follow-up. Adjust for: (1) comparability: (1) surgery stage 1 age (days), (2) birth weight (kg)/gastational age (weeks); (2) Figure 3: Forest plot of mortality outcomes between stage 1 and stage 2, and stage 2 and stage 3; hospital stay outcome after stage 1 and stage 2; and ICU stay after stage 1, 2, and 3. Right ventricle to pulmonary artery shunt vs. modifed Blalock-Taussig shunt.   14 Journal of Cardiac Surgery reoperation at S2P, and incidence of pulmonary artery stenosis prior to S2P.

Conclusions
Te RV-PA shunt had lower mortality and overall complications rate than mBT shunt at the short-term outcome within the frst two years, but at the long term, there was no diference between the two shunts. On the other hand, the mBTshunt had a lower incidence of cardiac complications at the early stage after the operations. However, some studies are poor due to the difculties in conducting original research in this feld. Terefore, we recommend conducting systematic reviews and original studies to compare these and other therapeutic procedures for these patients.