4 | DISCUSSION
In this study, a systematic review of 13 RCTs demonstrated that the use of MISA techniques could significantly reduce the incidence of BPD at 36 weeks, pneumothorax, and hsPDA without increasing the incidence of other neonatal complications compared with endotracheal intubation for surfactant delivery. MISA techniques also reduced the need for mechanical ventilation within 72 h of life or during hospitalization. Although MISA techniques increased the rate of surfactant reflux, they did not increase the need for additional surfactant, indicating that MISA techniques did not reduce the efficiency of surfactant.
In addition, there was no significant difference in the mortality rate between the two groups. On the one hand, the mortality rate was lower in the MISA group than that in the control group (9.1% vs. 12.1%), and it was right on the edge of statistical significance (p = .05), so further analysis is needed after additional RCT studies are published. On the other hand, the mortality rate was significantly reduced in the MISA group after sensitivity analysis (RR = 0.69, 95% CI : 0.51 to 0.95, p = .02). This reduction might have been due to the younger gestational age of subjects in the excluded study (gestational age, < 29 weeks) 14,19. The younger the gestational age, the higher the mortality rate 27,28. The effect of gestational age on mortality was greater than that of surfactant delivery techniques between the two groups. Overall, the results concluded here were robust to most sensitivity analyses.
Pneumothorax occurred less frequently in the MISA group than in the control group, considering that MISA techniques do not cause pressure or volume damage from brief mechanical ventilation. Similarly, the incidence of hsPDA in the MISA group was lower than that in the control group, suggesting that MISA techniques had fewer effects on hemodynamics. Epidemiological studies have reported that hsPDA associates with BPD 29. hsPDA increased the pressure of pulmonary capillary bed arteries and veins, resulting in more fluid infiltration into the pulmonary interstitium, which aggravated pulmonary edema. In this study, the incidence of hsPDA in the MISA group was lower than that in the control group, which might have been another reason for the low incidence of BPD.
The use of INSURE techniques for surfactant delivery has been widely reported in clinical practice, but many shortcomings remain30,31. Surfactant delivery in a noninvasive approach that reduces the hazards of endotracheal intubation, and it includes aerosolized administration 32, laryngeal mask airway–guided administration 33,34, pharyngeal administration 35, and minimally invasive pulmonary surfactant administration. However, due to the lack of relevant studies on the first three approaches, the results are inconsistent, and further studies are needed to evaluate their safety and effectiveness36,37. Compared with endotracheal intubation, the possible advantages of minimally invasive administration are as follows. Firstly, thin tubes can reduce damage to vocal cords and the tracheal mucosa 9. Secondly, MISA techniques can prevent lung injury in premature infants from high pressure or lung overdistension10,38. Finally, they allow uninterrupted application of NCPAP during surgery, thereby facilitating the maintenance of stable oxygen saturation 39.
This meta-analysis searched for RCT studies using a thin catheter for surfactant delivery and included LISA and MIST techniques, leading to differences from other meta-analyses. A previously published meta-narrative review failed to identify a lesser BPD at 36 weeks in the MISA group 40, but this study observed a reduction in BPD at 36 weeks, which was consistent with the conclusions of a mesh meta-analysis and a cross-sectional observational multicenter study41,42. In comparison with a recent meta-analysis43, after excluding the same two RCTs for sensitivity analysis, this study found a reduction in mortality, whereas the authors of the previously published meta-analysis did not.
Although we strived for a comprehensive and accurate meta-analysis, there were several limitations. First, there were differences in the gestational age and the body weight among the studies, and lung tissues at different stages of development showed different sensitivities to injury from mechanical ventilation, which might have affected the incidence of BPD at 36 weeks, pneumothorax, and other complications. Second, different doses and types of surfactant might have affected the outcome of the study. Due to the limited number of existing studies, it was difficult to evaluate the aforementioned factors in the groups, and additional large-sample, multi-center clinical studies are needed to further explore the efficacy and safety. Finally, none of the included studies reported long-term neurodevelopmental follow-up data.
In conclusion, the use of MISA techniques for surfactant delivery not only reduced the need for mechanical ventilation (within 72 h of life or during hospitalization), but also reduced the incidence of BPD at 36 weeks, pneumothorax, and hsPDA without increasing the incidence of other complications. Therefore, MISA techniques should be considered as part of the lung protective strategy for premature infants with NRDS. However, the specifics of these techniques are rarely reported and related large-sample multicenter studies are scarce. Therefore, additional well-designed, well-targeted RCT studies are needed to evaluate their efficacy and safety.
A CKNOWLEDGEMENT
We thank International Science Editing ( http://www.internationalscienceediting.com ) for editing this manuscript.
CONFLICT OF INTERESTS
The authors have no conflicts of interest to declare.
AUTHOR CONTRIBUTIONS
Xiaohong Wu and Zhoushan Feng conceptualized and designed research, collected and analyzed data, and drafted this article. Yiyu Lai and Juan Kong analyzed the data, reviewed the data, and revised the draft. Chunhong Jia and Zhanyuan Xu participated in design research, collecting and analyzing data. Yaoyong Chen, Qiliang Cui and Fan Wu supervised the elaboration of the research design, data analysis, and reviewed the manuscript. All authors have approved the final version of this article.