A systematic review and meta-analysis of pulmonary surfactant combined with budesonide in the treatment of neonatal respiratory distress syndrome
Original Article

A systematic review and meta-analysis of pulmonary surfactant combined with budesonide in the treatment of neonatal respiratory distress syndrome

Zongyan Yi1, Yajuan Tan1, Yang Liu1^, Ling Jiang1, Li Luo1, Liang Wang1, Wei Lei2, Jiping Tan2, Ruofen Yan2

1Department of Pediatrics, The Ethnic Hospital of Enshi Tujia and Miao Autonomous Prefecture, Enshi, China; 2Department of Nursing, The Ethnic Hospital of Enshi Tujia and Miao Autonomous Prefecture, Enshi, China

Contributions: (I) Conception and design: Z Yi; (II) Administrative support: Z Yi; (III) Provision of study materials or patients: Z Yi, Y Tan; (IV) Collection and assembly of data: Z Yi, Y Liu; (V) Data analysis and interpretation: Y Liu; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors.

^ORCID: 0000-0002-1406-3649.

Correspondence to: Yang Liu. The Ethnic Hospital of Enshi Tujia and Miao Autonomous Prefecture, No. 178, Aviation Avenue, Enshi 445000, China. Email: zongyanyi@126.com.

Background: Neonatal respiratory distress syndrome (NRDS), if caused by a lack of pulmonary surfactant (PS), leads to progressive alveolar collapse. Glucocorticoids have anti-inflammatory and anti-allergic effects and can reduce bronchial and pulmonary edema. This research hopes to systematically evaluate the efficacy and safety of animal-derived PS combined with the glucocorticoid drug budesonide in the treatment of NRDS.

Methods: Electronic databases (i.e., Wanfang, Weipu, CNKI, PubMed, Embase, Cochrane Library) were searched from inception until May 30th, 2021. Studies relevant to the treatment of pulmonary surfactant combined with budesonide in the treatment of neonatal respiratory distress syndrome were identified. Consequently, all the studies that met the inclusion criteria were considered qualified for screening. For the meta-analysis, all data were analyzed using RevMan 5.3 software. Furthermore, subgroup analysis was performed to evaluate the administration method of budesonide (nebulized inhalation, intratracheal instillation) combined with intratracheal instillation of pulmonary surfactant.

Results: A total of 10 articles were included in this study, involving 527 children. This meta-analysis suggests that the treatment of intratracheal infusion of pulmonary surfactant combined with budesonide therapy can effectively (I) reduce the time of mechanical ventilation (OR =−1.72,95% CI: −2.44 to −1.01, P<0.00001); (II) reduce the length of stay (OR =−5.17, 95% CI: −9.35 to −0.99, P=0.02); (III) reduce the incidence of bronchopulmonary dysplasia (BPD) (OR =0.52, 95% CI: 0.39–0.68, P<0.00001); and (IV) reduce the incidence of BPD (RR =0.73, 95% CI: 0.40–1.35, P=0.32). There was no significant difference in the incidence of retinopathy of prematurity (ROP), necrotizing enterocolitis (NEC), patent ductus arteriosus (PDA), or sepsis between the experimental group and the control group.

Discussion: The treatment of animal-derived pulmonary surfactant combined with budesonide can effectively shorten the hospital stay and reduce the time of invasive mechanical ventilation and the incidence of BPD. Meanwhile, it does not increase the risk of related complications or death. This approach can be applied clinically.

Keywords: Pulmonary surfactant; neonatal respiratory distress syndrome (NRDS); budesonide; meta-analysis

Submitted Nov 23, 2021. Accepted for publication Feb 18, 2022.

doi: 10.21037/tp-22-8

Instruction

Neonatal respiratory distress syndrome (NRDS), also known as neonatal hyaline membrane disease, is mainly caused by the lack of pulmonary surfactant (PS), leading to progressive alveolar collapse. Progressive dyspnea, groaning, cyanosis, and three-concave inhalation signs appear within 4 to 12 h after birth. In severe cases, respiratory failure may occur (1). The morbidity is related to gestational age. The smaller the gestational age, the higher the morbidity, and the lower the weight, the higher the mortality rate. Imaging examination is an important auxiliary method for the diagnosis and prognosis of NRDS, and it is of great significance for clinical treatment guidance to reduce neonatal mortality by means of imaging examination for the early identification and diagnosis of NRDS in a timely manner and effective treatment measures. Ultrasonography is widely used in clinical practice with the advantages of good safety, strong repeatability and easy operation (2). In recent years, lung ultrasound diagnosis and treatment technology has progressed with the continuous development of ultrasound technology, which can semi-quantitatively assess the ventilation status and lung water content of the lungs, so as to make judgments on the degree and nature of lung lesions, and become an important auxiliary diagnosis and treatment method for respiratory critical diseases (3). At present, the main methods for the treatment of NRDS are basic life support combined with mechanical ventilation and PS replacement therapy. However, there are still long periods of invasive mechanical ventilation, a high incidence of bronchopulmonary dysplasia (BPD), and long hospital stays. Glucocorticoids (GCs) have anti-inflammatory and anti-allergic effects, can reduce bronchial and pulmonary edema, promote the production of antioxidant enzymes and PS, and help improve lung function, thereby reducing the incidence of BPD (4). However, intravenous GCs have relatively large side effects and many complications, and intravenous administration is no longer recommended (5). Budesonide is a GC with strong local anti-inflammatory effects and fewer systemic adverse reactions. According to pharmacokinetic data, approximately 5–10% of budesonide may remain in the lungs after 1 week, and absorbed budesonide in the circulation is rapidly metabolized in the liver to 16-α-hydroxyprednisolone, and its GC activity is low. The half-life of oral budesonide through blood clearance is approximately 4 h (6), which is shorter than the half-life of most GCs. Various animal studies have shown that intratracheal administration of surfactants and GCs can improve lung function (7-10). Direct intratracheal administration of budesonide alone has not been proven effective (11). A previous study showed that inhalation of budesonide can reduce the incidence of death or BPD in low-birth-weight infants (12). Preliminary studies have shown that after instilling pulmonary surfactant and budesonide into the trachea, more than 80% of budesonide may stay in the lungs for up to 8 h (6). Study has shown that the combined use of budesonide and lung surfactants can increase the solubility of budesonide in the lungs, thereby increasing the efficiency of budesonide use (13). Budesonide is not decomposed by lung cells but is extensively combined with fatty acids to form budesonide esters (14). This reversible combination may prolong its local anti-inflammatory effect in the lungs, which may explain why budesonide can be effective for several days even with only one or two doses (6). This article aims to evaluate the safety and effectiveness of pulmonary surfactant combined with budesonide in the treatment of neonatal respiratory distress syndrome through a meta-analysis, which can provide an evidence-based strategy for clinical diagnosis and treatment. Unlike previous study of basic life support combined with mechanical ventilation and PS replacement therapy (2), the analysis of pulmonary surfactant combined with budesonide, a minimally traumatic therapy, may provide a new basis for future clinical treatments and reduce neonatal morbidity and mortality. We present the following article in accordance with the PRISMA reporting checklist (available at https://tp.amegroups.com/article/view/10.21037/tp-22-8/rc).

Methods

Search strategy

Relevant studies published until May 30th, 2021 pertaining to the treatment of pulmonary surfactant combined with budesonide in NRDS were searched in online databases such as Wanfang, Weipu, CNKI, PubMed, Embase, and Cochrane Library. In the current study, articles were identified by utilizing the following Chinese keywords: “Neonatal respiratory distress syndrome, Neonatal hyaline membrane disease”, “Pulmonary surfactant, alveolar surfactant”, “Budesonide, glucocorticoid” and English keywords “exogenous surfactant”, “pulmonary surfactant”, “Budesonide”, “hyaline membrane disease of newborn”, “neonatal respiratory distress syndrome”, “neonate respiratory distress syndrome”, and “newborn respiratory distress syndrome”. In PubMed, for example, the search strategy was as follows:

  • #1 (exogenous surfactant) OR (pulmonary surfactant)) OR (pulmonary surfactants));
  • #2 (hyaline membrane disease of newborn)) OR (neonatal respiratory distress syndrome)) OR (neonate respiratory distress syndrome)) OR (newborn respiratory distress syndrome));
  • #3 (Budesonide);
  • #1 and #2 and #3.

Study criteria and selection

Publications related to pulmonary surfactant combined with budesonide in the treatment of NRDS were searched.

Studies that met the following criteria were included: (I) randomized controlled trial (RCT); (II) the subjects were premature infants with obvious clinical symptoms or imaging evidence of respiratory distress; (III) the intervention method of the experimental group was PS endotracheal dripping combined with budesonide treatment, and the PS type was animal-derived lung surfactant extract; (IV) the control group was treated with pulmonary surfactant dripping into the trachea, and the PS type was animal-derived pulmonary surfactant extract; (V) at least one primary or secondary outcome measure set out in this paper was reported.

The exclusion criteria were as follows: (I) non-RCT studies; (II) duplicate articles; (III) papers that cannot extract, transform, or retrieve data; (IV) review or systematic evaluation of articles; (V) studies with vague outcome indicators and obvious data errors; (VI) studies irrelevant to the theme or papers that were not open access.

Data extraction and management

Duplicate documents were removed, and the remaining articles were independently screened by two reviewers based on the main content of the abstract. Independent reviewers give suggestions on the article and discussed the acceptability of the article. Independent reviewers standardized the data of the article as follows: (I) first author and publication year; (II) general information; (III) intervention mode; (IV) outcome indicators.

Quality assessment

The quality of RCTs included in the study was assessed using the Cochrane risk of bias tool. The tool includes five items: evaluation of random sequence generation and allocation hiding, blinding of participants and personnel, blinding of result evaluation, and selective reporting bias. Then, studies in each field were divided into three categories: “low risk”, “high risk” and “unclear risk”.

Statistical analysis

All data were analyzed using Review Manager 5.3 software. Cochran Q statistics and I2 statistics were used to assess heterogeneity. Random effects models and fixed effects models (P>0.1 and I2<50%) were used to assess heterogeneity.

Results

Study selection

We retrieved 636 studies from PubMed, Wangfang, and CNKI. After removing duplicate documents, 255 articles were included in the screening of article content; 381 articles were excluded by excluding abstracts or titles that did not meet the requirements. Of the remaining 86, 68 studies that did not fit the type of study and had missing data were excluded. The remaining 10 eligible studies were included in the analysis (Figure 1).

Figure 1 Flowchart for the search strategy and study selection process. *, PubMed, Wanfang, and CNKI. **, non-RCT studies; duplicate articles; papers that cannot extract, transform, or retrieve data; review or systematic evaluation of articles; studies with vague outcome indicators and obvious data errors; studies irrelevant to the theme or papers that were not open access.

General information

The subjects of this study were premature infants diagnosed with RDS after birth. Among the 10 articles that met the criteria, 8 of them included 977 cases in total. The experimental group (PS and budesonide mixture intratracheal dripping) included 480 cases vs. the control group which included 497 cases. In the other two studies, a total of 200 subjects were studied. The experimental group (100 cases) was treated with tracheal PS and budesonide atomization inhalation, while the control group (100 cases) was treated with tracheal PS only. The basic characteristics of the included literature are shown in Table 1.

Table 1

Characteristics of randomized control trials included in this meta-analysis

Author and publication year T/C (n) Gestational weeks Weight of birth (g) Intervention
Trial group control Trial group control Usage and dosage of trial Usage and dosage of control
Yeh (15), 2016 131/134 26.5±2.2 26.8±2.2 882±249 935±283 PS (poractant alfa injection 100 mg/kg) with budesonide (0.25 mg/kg), tracheally PS (poractant alfa injection 100 mg/kg) tracheally
Siqi Chen (16), 2019 52/50 30.84±1.78 31.03±1.96 1,556.54±350.44 1,589.40±462.71 PS (poractant alfa injection 100 mg/kg, 150–200 mg/kg) with budesonide (0.25 mg/kg), tracheally PS (poractant alfa injection 150–200 mg/kg) tracheally
Bo Yang (17), 2021 97/101 30.6±1.6 30.8±1.7 1,535±351 1,540±340 PS (phospholipid of bovine 88.2±37.3 mg/kg) with budesonide (0.25 mg/kg), tracheally PS (phospholipid of bovine 88.5±44.6 mg/kg) tracheally
Jing Pan (18), 2017 15/15 29.5±1.8 30.0±1.7 1,260±240 1,360±370 PS (phospholipid of bovine 70 mg/kg) with budesonide (0.25 mg/kg), tracheally PS (phospholipid of bovine 70 mg/kg) tracheally
Lijing Deng (19), 2018 18/28 <37 <37 <1,500 <1,500 PS (poractant alfa injection 150 mg/kg) with budesonide (0.25 mg/kg), tracheally PS (poractant alfa injection 150 mg/kg) tracheally
Jingzhen Su (20), 2019 48/50 29.68±1.55 29.16±1.45 1,351.35±337.77 1,211.8±267.78 PS (poractant alfa injection 200 mg/kg) with budesonide (0.25 mg/kg), tracheally PS (poractant alfa injection 200 mg/kg) tracheally
Yiping Zhou (21), 2019 55/55 29.37±1.22 29.43±1.25 1,287.14±209.25 1,256.84±204.81 PS (poractant alfa injection 150 mg/kg) with budesonide (0.25 mg/kg), tracheally PS (poractant alfa injection 150 mg/kg) tracheally
Lili Ping (22), 2019 64/64 29.1±1.24 28.93±1.2 1,264.93±207.12 1,260.33±205.87 PS (poractant alfa injection 150 mg/kg) with budesonide (0.25 mg/kg), tracheally PS (poractant alfa injection 150 mg/kg) tracheally
Yazhou Wang (23), 2018 72/72 31.42±4.27 31.51±4.16 1,934.54±282.26 1,972.54±275.34 PS (poractant alfa injection 100 mg/kg) tracheally with budesonide (0.25 mg/kg), aerosol inhalation, 3 days PS (poractant alfa injection 100 mg/kg) tracheally
Yaoshuang Wang (24), 2019 28/28 29.51±0.23 29.49±0.27 1,320±150 1,290±210 PS (phospholipid of bovine 70 mg/kg) tracheally, with budesonide (0.5 mg +2 mL normal saline aerosol inhalation, 3 days PS (phospholipid of bovine 70 mg/kg) tracheally

PS, pulmonary surfactant.

Quality assessment of included studies

The Cochrane Risk Bias assessment tool was used to evaluate the quality of the studies. All 10 papers were randomly grouped, of which 2 papers described the random grouping methods and allocation concealment specifically, and the remaining 8 only mentioned random grouping but did not describe the specific grouping method. Only 1 paper implemented triple blinding. None of the 10 papers had preset outcome indicators missing. Only 3 articles described dropouts and losses to follow-up. The results of the bias assessment of the included literature are shown in Figure 2.

Figure 2 Summary of risk of bias of included studies.

Results of meta-analysis of outcome indicators

Effect of pulmonary surfactant combined with budesonide on invasive mechanical ventilation time in infants with NRDS

Among the included studies, 9 studies reported the duration of invasive mechanical ventilation, and a total of 912 children were included, including 449 in the experimental group and 463 in the control group. The statistical results showed that P<0.00001, I2=91%, so the random effect model was adopted. Meta-analysis results showed that pulmonary surfactant combined with budesonide in the treatment of NRDS could effectively reduce the duration of invasive mechanical ventilation, with statistical significance between the two groups (OR =−1.72, 95% CI: −2.44 to 1.01, P<0.00001). Subgroup analysis was conducted according to different administration methods. The time of invasive mechanical ventilation in the tracheal dripping subgroup was significantly different from that in the control group, and the combined effect value of the random effect model was OR =−1.30 (95% CI: −1.72 to −0.88, P<0.00001). The duration of invasive mechanical ventilation in the atomized inhalation subgroup was shorter in the experimental group than in the control group, but the difference was not statistically significant, and the combined effect value of the random effect model was (OR =−3.24, 95% CI: −6.60 to 0.13, P=0.06), which is shown in Figure 3.

Figure 3 Meta-analysis of invasive mechanical ventilation time in infants with NRDS. NRDS, neonatal respiratory distress syndrome; SD, standard deviation; IV, independent variable; CI, confidence interval.

Effect of pulmonary surfactant combined with budesonide on the incidence of BPD in children with NRDS

Among all the included studies, 8 studies reported the incidence of BPD. A total of 1,075 children were included, including 534 in the experimental group and 541 in the control group. The statistical results showed that (P=0.55, I2=0%), so a fixed-effect model was adopted. Meta-analysis results showed that pulmonary surfactant combined with budesonide treatment of NRDS could significantly reduce the incidence of BPD, and there was statistical significance in the incidence of BPD between the experimental group and the control group (OR =0.52, 95% CI: 0.39–0.68, P<0.00001). Subgroup analysis was conducted according to different administration methods, and the incidence of BPD in the tracheal dripping subgroup was significantly different from that in the control group, while the combined effect value of the fixed effect model was OR =0.52, 95% CI: 0.39–0.70, P<0.0001. The incidence of BPD in the atomized inhalation subgroup was lower in the experimental group than in the control group, but the difference was not statistically significant, and the combined effect value in the fixed effect model was OR =0.46, 95% CI: 0.19–1.12, P=0.09. The details are shown in Figure 4.

Figure 4 Meta-analysis of the incidence of BPD in children with NRDS. BPD, bronchopulmonary dysplasia; NRDS, neonatal respiratory distress syndrome; CI, confidence interval.

Effect of pulmonary surfactant combined with budesonide on length of hospital stay in infants with NRDS

In all the included studies, 7 studies reported the length of hospital stay, and a total of 738 newborns were included, including 362 in the experimental group and 376 in the control group. The statistical results showed P<0.00001, I2=90%, so a random-effects model was adopted. Meta-analysis showed that pulmonary surfactant combined with budesonide could significantly reduce the length of hospital stay for NRDS (OR =−5.17, 95% CI: −9.35 to −0.99, P=0.02). The duration of hospital stay in the experimental group was shorter than that in the control group, but the difference was not statistically significant. The combined effect value of the random effect model was OR =−4.25 (95% CI: −8.72 to 0.21, P=0.06). The length of hospital stay of the atomization subgroup was significantly different from that of the control group, and the combined effect value of the random effect model was OR =−10.35 (95% CI: −14.18 to −6.52, P<0.00001). The details are shown in Figure 5.

Figure 5 Meta-analysis of length of hospital stay in infants with NRDS. NRDS, bronchopulmonary dysplasia; SD, standard deviation; IV, independent variable; CI, confidence interval.

Effect of pulmonary surfactant combined with budesonide on the mortality of infants with NRDS

Five studies reported 693 deaths in total, including 343 in the experimental group and 350 in the control group. The statistical results showed that P=0.62, I2=0%, so the fixed-effect model was adopted. Meta-analysis showed that pulmonary surfactant combined with budesonide could reduce the mortality rate of NRDS, but there was no significant difference. The combined effect value of the fixed effect model was OR =0.64 (95% CI: 0.35–1.14, P=0.13). All five studies were administered intratracheally, and no deaths were reported in the aerosol inhalation study, so a subgroup analysis was not required (Figure 6).

Figure 6 Meta-analysis of mortality of infants with NRDS. NRDS, bronchopulmonary dysplasia; CI, confidence interval.

Effect of pulmonary surfactant combined with budesonide on other complications in infants with NRDS

There was no significant difference in the incidence of related complications, such as retinopathy of prematurity (ROP), necrotizing enterocolitis (NEC), patent ductus arteriosus (PDA) and septicemia, between the experimental group and the control group (all P values were greater than 0.05). Pulmonary surfactant combined with budesonide does not increase the risk of complications associated with NRDS (Table 2).

Table 2

Meta-analysis of other indicators of infants with NRDS

Outcome indicators Articles Heterogeneity Experimental group Control group OR (95% CI) P
ROP (6-8,11-13) P=0.35, I2=10% 89/447 88/454 1.03 (0.73–1.47) 0.85
NEC (6-8,11-13) P=0.79, I2=0% 41/447 37/454 1.14 (0.70–1.83) 0.60
PDA (6,7,11) P=0.07, I2=62% 60/231 88/234 0.59 (0.28–1.24) 0.17
Sepsis (6,8,12,13) P=0.71, I2=0% 37/347 53/354 0.66 (0.42–1.06) 0.08

NRDS, bronchopulmonary dysplasia; ROP, retinopathy of prematurity; NEC, necrotizing enterocolitis; PDA, patent ductus arteriosus; OR, odds ratio; CI, confidence interval.

Discussion

Effect of pulmonary surfactant combined with budesonide on invasive mechanical ventilation time, the incidence of BPD, hospital stay and other complications in infants with NRDS

The common cause of NRDS is premature delivery, which can cause heart failure and brain developmental disorders in severe cases. We can quickly and accurately diagnose NRDS by examining the patient’s clinical symptoms, changes in lung X-rays, and lung maturity. Clinically, mechanical ventilation is generally given. However, the lungs of premature babies are not fully developed, and mechanical ventilation will cause varying degrees of damage to the lung tissue structure, leading to a large amount of tissue fiber growth, a decrease in the number of alveoli, and an increase in lung resistance, resulting in a severe decline in lung function. The injured lung is susceptible to bacterial invasion and infection, leading to long-term reliance on ventilators or weaning difficulties, prolonging the hospitalization time of children, increasing the incidence and mortality of BPD, and increasing the risk of infection due to other complications. In this article, a meta-analysis of the results of the included 10 studies showed that the duration of mechanical ventilation and hospitalization of children in the experimental group was shortened, and the incidence of BPD was reduced. This is consistent with the conclusion of Yan that other pulmonary surfactant combined with budesonide can quickly improve the lung function of children with NRDS so that the ventilator can be withdrawn as soon as possible (25). After pulmonary surfactant is injected into the lungs, under the influence of lung surface tension, it quickly disperses on the surface of the alveoli, promoting the expansion of atrophic alveoli, establishing an effective gas exchange platform, reducing the lung resistance of the child, and improving the functional level of the lungs, which shortens the time of mechanical ventilation and the length of hospitalization. In addition, budesonide can fight local inflammation, has good anti-inflammatory and antiviral effects in local lung tissues, and inhibits the occurrence of lung inflammation. During the inhalation process, it cannot be ensured that all the drugs will be delivered to the deep alveoli of the child, which might cause part of the drug to be suspended on the wall of the tracheal tube in granular form, thus reducing the efficacy or causing irritation to the local lung tissue. Pulmonary surface-active substances have the effect of reducing the surface tension of the alveoli and can evenly distribute the drug in the lungs, promoting its absorption of budesonide and therefore playing a dual role in the drug effect, which improves the clinical efficacy. The statistical analysis of the mortality of the two groups showed that the difference between the experimental group and the control group was not statistically significant. The analysis of complications related to neonatal respiratory distress syndrome suggested that the difference between the experimental group and the control group was not statistically significant. A short-term follow-up did not find any GC-related sequelae in the experimental group. In summary, pulmonary surfactant combined with budesonide in the treatment of NRDS will not increase the incidence of death and complications, and its clinical application is relatively safe. Therefore, for patients with suitable conditions in clinical treatment, clinicians can consider alveolar surfactant combined with budesonide to treat neonatal respiratory distress syndrome.

Administration methods of budesonide and their therapeutic effect in children with NRDS

In the 10 studies included in this article, budesonide was an inhaled preparation, and the way budesonide was used was not uniform. Two of the articles used aerosol inhalation, and the other 8 used intratracheal instillation. According to the analysis of different administration methods, the subgroup analysis showed that the tracheal instillation subgroup was significantly better than the control group in reducing the time of mechanical ventilation, while the difference in the nebulization group was not statistically significant in reducing the length of hospitalization. The length of hospital stay in the experimental group was significantly less than that in the control group, while the tracheal instillation subgroup had statistically significant differences in the length of stay compared to the experimental group. The subgroup with tracheal instillation demonstrated statistical significance in the reduction and prevention of the occurrence of BPD, and the results within the subgroups were inconsistent. This phenomenon was related to the small sample size. Yang and other scholars proved through piglet model experiments that the combination of surfactant and budesonide intratracheal instillation can improve the lung histological structure of premature piglets and concluded that the combination of intratracheal corticosteroid surfactant is effective in alleviating lung diseases. Thereafter, they concluded that severe RDS could be treated (26). Cole et al. believes that it is difficult for premature infants to inhale budesonide into the alveoli by aerosols, and the anti-inflammatory effect is easily limited. However, direct intratracheal infusion of PS and budesonide can increase the concentration of budesonide in the alveoli, thereby increasing the anti-inflammatory effect (27). However, Hua et al. believe that aerosol budesonide is more easily absorbed in the lungs, and inhalation can allow the maintenance of a certain drug concentration in the lungs, which is conducive to full absorption and function in the lungs (28). Neonatal respiratory distress is caused by a lack of surfactant, long-term respiratory distress may eventually lead to bronchopulmonary dysplasia. At present, study has shown that budesonide-surfactant endotracheal administration is used to prevent infant BPD (10). Intra-tracheal administration of budesonide-surfactant combination was associated with decreased incidence of BPD alone or composite outcome of death or BPD in very low birth weight (VLBW) infants (29). It is further shown that budesonide-surfactant neonatal long-term respiratory distress has a clear clinical advantage in the prevention of infant BPD, providing an evidence-based basis for the treatment of neonatal respiratory distress. Since there were only two studies in the nebulization inhalation group in this article and the sample size was small, no statistical study between subgroups was carried out. However, compared with the control group, the instillation group was more statistically significant in improving the time of mechanical ventilation and reducing the incidence of BPD in the treatment of neonatal respiratory distress than the non-aerosolized inhalation group. Based on the research in this article, we recommend the use of these treatments in clinical practice.

Limitations of this research

Compared with other studies related to neonatal respiratory diseases, the innovation of this study is to focus on the clinical medication of neonatal distress syndrome, and elaborate on the results of budesonide treatment. Due to the small sample size that fits the included studies, the ethnic group involved in the study was relatively limited (China, the United States), most of the included studies did not describe data blindness, and the reported data may have selectivity bias. In addition, there is no uniform standard for drug dosage and frequency of medication in the current administration method. It is still necessary to further develop multicenter, large-sample and blind clinical experimental studies to provide a medical basis for the comprehensive evaluation of the efficacy and safety of pulmonary surfactant combined with budesonide in the treatment of NRDS.

Acknowledgments

Funding: This research was funded by the Guiding Project of Science and Technology Bureau of Enshi Prefecture, Hubei Province (No. E20200018).

Footnote

Reporting Checklist: The authors have completed the PRISMA reporting checklist. Available at https://tp.amegroups.com/article/view/10.21037/tp-22-8/rc

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tp.amegroups.com/article/view/10.21037/tp-22-8/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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Cite this article as: Yi Z, Tan Y, Liu Y, Jiang L, Luo L, Wang L, Lei W, Tan J, Yan R. A systematic review and meta-analysis of pulmonary surfactant combined with budesonide in the treatment of neonatal respiratory distress syndrome. Transl Pediatr 2022;11(4):526-536. doi: 10.21037/tp-22-8

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