We conducted a comprehensive search for studies of patients with PAH-CHD who underwent correction. The literature was searched using MEDLINE, CNKI, WAN FANG, and Cochrane Library (up to December 2020). The screening methods of the three times are presented in Table 1.

We counted 235 cases of PAH recurrence between interventional closure and surgery. To further understand this difference, we performed the literature search by criterion 1. Firstly, the mean, sd, and n values of PAH in the study were formally adjusted and compared between preoperative, postoperative, and follow-up groups (Li and Li, 2020). Secondly, we performed a conventional meta-analysis to compare the therapeutic and prognostic outcomes of different operations. Differences were assessed by odds ratio (OR) with 95% confidence intervals (CIs). The possibility of publication bias was estimated using funnel plots. Heterogeneity among studies was evaluated by calculating p-value and the I ² measure of inconsistency, which was considered significant if p < 0.10 and I ² > 50%. All calculations were carried out using Review Manager 5.3 (The Nordic Cochrane Center, Copenhagen, Denmark).

We reviewed the instructions for use of sildenafil and bosentan to ensure correct dosing. The literature was screened according to the criterion 2. At the same time, the dose of the two drugs was calculated according to the patient’s body surface area. The therapeutic and prognostic effects of three doses of sildenafil and bosentan were compared, including body surface dose (DBSA), literature dose (DL), and case review (DCR). Literature was screened according to the criterion 3 to compare the postoperative oral efficacy of the two drugs.

We divided 235 patients into five groups, namely infants (<1 year), toddlers (1–6 years), children (7–14 years), adolescents (15–17 years), and adults (≥18 years). Recurrence, preoperative PAH, and treatment outcomes were analyzed for each group.

Statistical analysis was performed using t-test and ANOVA. The t-tests and graphs of each drug safety indicators were applied in GraphPad Prism 8 (GraphPad Software, San Diego, Canada). Results were considered statistically significant when the p-value was <0.05.

Echocardiography of pre-treatment PAH was performed in 10 patients only and was not included in the analysis of PAH results. From a review of 224 cases, the recurrence rate of PAH of surgery (50.83%, n = 172) was higher than that of interventional closure (41.26%, n = 52). We selected nine Chinese literature about patients with PAH-CHD who underwent correction according to criterion 1 (Table 3) (Zhang et al., 2012; Jing, 2013; Zhao, 2013; Cao et al., 2016; Jing et al., 2016; Sun et al., 2016; Zhang et al., 2016; Chao and Zhao, 2017; Wang et al., 2020). In Table 3, we also recorded the PAH of both groups in this case review.

As shown in Figure 3, similar trends in PAH in the case review and literature: 1) PAH decreases significantly after treatment, which was statistically significance (p < 0.05). The decrease in PAH after surgery was more significant than in the interventional closure group. 2) PAH decreased during follow-up in the interventional closure group, but was not statistically significant in the case review, whereas it was statistically significant in the literature (p < 0.05). 3) PAH increased during follow-up in all surgical groups (p < 0.05). According to the meta-analysis (Figure 4), closure and surgery are feasible to reduce PAH in patients with PAH-CHD (p < 0.10, I ² > 50%). Pulmonary artery pressure control was poor in the postoperative group (I ² < 50%), whereas it was good in the closed group (p < 0.10, I ² > 50%).

In order to study the appropriate dose, we selected seven literature through criterion 2 (Table 4) (Mohamed and Ismail, 2012; Steinhorn et al., 2016; Omar et al., 2016; Hernando and Amed, 2006; Sinan et al., 2011; Robyn et al., 2011; Carmine et al., 2017). According to the literature, we listed the corresponding body surface area with different body weights and the calculated dose of two drugs based on the body surface area (Li, 2010). As shown in Figure 5, the actual doses of bosentan and sildenafil were insufficient when compared with the dosage in the literature and surface area calculated. The dosage in consistent with the literature and the dosage in inconsistent with the literature were divided into two groups. It was found that the literature group still had a statistically significant reduction in PAH after 30 to 60 days of follow-up (p < 0.05). On the other hand, the group that did not follow the literature dosage showed a sustained increase in PAH after 30 days of follow-up.

In order to study the postoperative treatment effect of these two drugs, two literature were screened out by criterion 3. Since no literature was found on postoperative combination therapy (sildenafil and bosentan), this study focused only on the effect of postoperative sildenafil monotherapy (Cheng et al., 2014; Yang, 2014). We found a statistically significant reduction in PAH in both the literature group of sildenafil and the case review group with combination therapy (p < 0.05). Bosentan reduced PAH only in the literature group, which was statistical difference in Figure 6 (p < 0.05).

We divided 235 patients into five groups (48 infants, 46 toddlers, 47 children, 22 adolescents, and 72 adults) (Table 5). The number of minors hospitalized for PAH-CHD was twice as many as adults (163:72). The best treatment outcome (36.14 mmHg) and the lowest recurrence rate (0.15%) were observed mainly in infants.

Combined with the literature and the case review in this study, surgery is inferior to closure. This phenomenon is widespread. The reason for this phenomenon might due to surgery requiring open chest and extracorporeal blood circulation. In contrast, the closure is less invasive and reduces the risk of infection. In this study, although the inclusion criterion for three times literature retrievals were consulted English and Chinese, almost most of the included literature was in Chinese (Suzuki et al., 2017; Akagi et al., 2018; Zwijnenburg et al., 2018). This might be because Chinese researchers might be more concerned with the follow-up of postoperative PAH, while researchers in other countries might pay more attention to the outcome of the operation itself. To improve patient survival, we believe that the postoperative follow-up of patients with PAH-CHD (detection of adverse factors and timely intervention) is very important. We hope that more researchers studying PAH will focus on the long-term postoperative follow-up to optimize the treatment and even provide a basis for treatment recommendations for patients with PAH-CHD.

The effect of combination therapy (bosentan and sildenafil) was more effective than that of bosentan. This result is consistent with the results of meta-analysis (Li et al., 2020). We propose that the main reason for poor postoperative control might be caused by insufficient dose and inappropriate medication. Most of the patients with PAH-CHD in our hospital were pediatric patients. Unfortunately, The drug dosage of these patients was not indicated on the packaging of bosentan and sildenafil. The commonly used method to determine the dosage of pediatric medicine is to convert it according to body weight, body surface area, or adult dosage. One study argued that doses should be calculated according to the 2/3 power of body weight (West, 2018). For example, Bosentan 60 kg adult dose is 250 mg/day, then the daily dose for a 10 kg toddler is 250/(60/10)^2/3 ≈ 75 mg. However, no matter which method is used to calculate, the dosage of drugs in some patients was far from adequate. We also consider the efficacy of controlling postoperative pulmonary arterial pressure by standardizing patient dosing, which requires further study.

The younger the patient’s age, the more effective the reduction in PAH. As the patient ages, the CHD might lead to cardiac remodeling and pulmonary artery function. Also, Also, damage to multiple organs may occur in the body due to chronic hypoxia, and a sudden increase in oxygen saturation does not reverse the damage. Therefore, we strongly recommend early operation (closure or surgery) for patients with CHD to improve the recovery outcome.