Vibrating Mesh Nebulizers vs. Less Invasive Surfactant Administration in the Treatment of Preterm Respiratory Distress Syndrome: A Multicenter, Open-label, Randomized Clinical Trial

Vibrating Mesh Nebulizers vs. Less Invasive Surfactant Administration in the Treatment of Preterm Respiratory Distress Syndrome: A Multicenter, Open-label, Randomized Clinical Trial | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Vibrating Mesh Nebulizers vs. Less Invasive Surfactant Administration in the Treatment of Preterm Respiratory Distress Syndrome: A Multicenter, Open-label, Randomized Clinical Trial Yiyao Jiang, Xin Chen, Runa Li, Hui Wang, Hanqing Wang, Qian Guo, and 7 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6488329/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Deficiency of pulmonary surfactant (PS) induces the onset of neonatal respiratory distress syndrome, which can lead to progressively worsening respiratory failure and even death. However, studies on improving lung function via the use of vibrating mesh nebulizer (VMN) technology to deliver PS to premature infants with NRDS are limited. This prospective multicenter, open-label, exploratory, randomized clinical trial, including 2 parallel groups and a 1:1 allocation, was conducted in 7 hospitals from Jan. 1, 2023, to Dec. 31, 2024. Premature infants born at less than 32 weeks of gestation and weighing less than 1500 g who presented after birth with RDS with the need for noninvasive ventilatory support as initial treatment were eligible for inclusion. Of the 49 eligible premature infants, 25 infants were randomized to the VMN group, and 24 infants were randomized to the LISA group. The main objective was to investigate the need for mechanical ventilation via an endotracheal tube (MVET) within 72 hours and the incidence of apnoea of prematurity, arrhythmia, and transient decrease in oxygen saturation. We did not find difference in need of MVET within 72 hours between VMN and LISA group (3 [12%] vs. 5 [20.8%]; odds ratio, 0.52; 95% confidence intervals, 0.11-2.46; P = 0.653). Comparing the LISA group, the incidence of apnoea of prematurity, arrhythmia, and transient decrease in oxygen saturation was lower in VMN group (all P <0.05). Conclusion: In this clinical trial, the noninvasive technique of VMN is a feasible and safe method for delivering PS. However, there was no difference between VMN and LISA in the efficacy of neonate RDS. Further RCTs are needed to test whether VMN can replace LISA in the treatment of RDS. Trial registration: ChiCTR2300072262 (https://www.chictr.org.cn), registered on 08/06/2023. Respiratory distress syndrome Preterm Infants Vibrating mesh nebulizers Figures Figure 1 What is Known LISA is commonly used for treatment of RDS in preterm neonates. VMN has been introduced as a newer approach to deliver PS for the treatment of NRDS. What is New: Compared with LISA, the noninvasive technique of VMN can be a safe way for delivering PS to preterm infants with RDS without significant adverse effects. There was no difference between VMN and LISA in the efficacy of neonate RDS. Introduction Respiratory distress syndrome (RDS), caused by PS deficiency, is considered a major cause of early mortality and poor long-term prognosis in premature neonates. 1 The incidence of neonatal RDS ranges from 5–60% in preterm neonates. 2 According to European consensus guidelines on the management of RDS, exogenous PS administration combined with mechanical ventilation can significantly reduce the mortality rate of RDS. 3 The classical route of PS administration involves injection into the lungs via endotracheal intubation. However, this procedure is invasive and can cause adverse effects in premature neonates. Thus, minimally invasive or noninvasive routes of PS delivery continue to be a popular research topic. 4 Innovative strategies such as nasal continuous positive airway pressure (NCPAP) combined with PS delivery techniques, such as intubation-surfactant-extubation (INSURE) and less invasive surfactant administration (LISA), have been widely used to treat RDS. 5 , 6 Although these techniques have reduced the need for mechanical ventilation, these methods are still essentially invasive. The use of VMN is a noninvasive way to further optimize PS delivery via inhalation. Compared with INSURE and LISA, VMN forms PS into atomized particles and facilitates PS deposition in the alveoli for the treatment of RDS in premature infants, with theoretically greater advantages. Berlinski comprehensively summarized the characteristics of VMN and their application in children. 7 However, evidence from clinical trials related to the use of VMN for the treatment of RDS in preterm infants is lacking. Therefore, we conducted this multicenter, open-label, randomized clinical trial to explorate the efficacy and safety of PS inhalation via VMN for the treatment of RDS in premature neonates. Methods Study Design This prospective multicenter, open-label, exploratory, RCT was a 2 parallel-group design with a 1:1 allocation ratio and was performed between January 2023 and December 2024. A total of 7 tertiary referral NICUs in China participated in this trial. Ethical review approval was obtained from the medical ethics committees of each of the 7 participating centers, and this study was registered with the Chinese Clinical Trial Registry (ChiCTR2300072262). The study was conducted in accordance with the protocol (Supplement 1) and followed the tenets of the Declaration of Helsinki. Only children whose legal guardians provided written informed consent were enrolled. This manuscript followed the Consolidated Standards of Reporting Trials (CONSORT) guidelines. Study Population Attending neonatologists screened the neonates daily for eligibility. The inclusion criteria were as follows: (1) gestational age between 25 and 32 weeks; (2) weight less than 1500 g; (3) gradually aggravated dyspnea after birth that met the diagnostic criteria for neonatal RDS as assessed by chest radiography; and (4) the need for noninvasive ventilatory support as initial treatment after birth. Neonates were excluded if they had one of the following conditions: (1) lack of effective spontaneous breathing; (2) indications for invasive ventilation, including fraction of inspired oxygen (FiO 2 ) > 0.4, arterial partial pressure of oxygen (PaO 2 ) 65 mmHg and pH < 7.25; (3) major congenital anomalies or chromosomal abnormalities; (4) neuromuscular diseases; or (5) suspected congenital lung diseases, malformations, or pulmonary hypoplasia. Intervention VMN Group The VMN was purchased from Aerogen Co., Ltd. (Ireland). Premature neonates were placed in the supine position to keep the airway open. While the infant was breathing via NCPAP ventilation, the VMN was connected to the inhalation tube of the ventilator via a T-tube. The VMN controller was connected to a nebulizing device. PS was injected into the container of the nebulizing device. Then, the controller was turned on, and nebulized aerosols were produced. If the drug became viscous or stagnant during nebulization, it was diluted with an appropriate amount of sterilized water for injection to complete nebulization. LISA Group Neonatologists and nurses at each hospital received training to ensure the homogeneity and safety of the LISA technique. While the infant was on NCPAP ventilation, a 6 Fr feeding tube was placed in the trachea via direct laryngoscopy with Magill forceps. The distance (cm) from the end of the feeding tube to the infant's mouth was calculated as follows: weight (kg) + 6. Once the correct position was confirmed, the tube was fixed to the upper jaw of the infant, and slow and continuous PS delivery was initiated. The tube was removed after PS delivery. PS dosage and the Criterion of re-intubation In both groups, the dosage of PS (Chiesi Pharmaceutical Co., Ltd, Italy) was 200 mg/kg. Arterial blood gas levels were measured before and 30 minutes after PS delivery, and the changes in these levels were calculated. The re-intubation criteria were as follows: (1) recurrent apnoea > 3 times per hour and heart rate 0.4 and PaO 2 60mmHg and pH < 7.20; (5) contraindications to non-invasive ventilation such as pulmonary haemorrhage, severe arrhythmia, shock, frequent convulsions, neonatal NEC, intestinal obstruction, etc. Randomization Eligible premature neonates were randomized (1:1) to either the VMN group or the LISA group. The randomization code was generated via a web-based computer-generated randomization tool ( https://www.randomizer.org ). An independent statistician prepared the randomization schedule in permuted blocks of 2, 4 or 6. The group assignments were placed in sequentially numbered, sealed, opaque envelopes that were opened only after consent was obtained from the parents. Assessments Arterial blood gas analysis results, including pH, PaCO 2 , and PaO 2 /FiO 2 , were compared between VMN group and LISA group. The primary outcomes were (1) the need for MVET within 72 hours after the initiation of NCPPV treatment, (2) the occurrence of bronchopulmonary dysplasia (BPD), and (3) death in the hospital. The secondary outcomes included apnoea of prematurity (AoP), arrhythmia, oxygen saturation < 85%, pneumothorax, periventricular leukomalacia (PVL), retinopathy of prematurity (ROP), necrotizing enterocolitis (NEC), periventricular or intraventricular hemorrhage (PVH-IVH), and the reapplication of PS. For the two groups, the arterial blood gas analysis and primary outcomes were used to evaluate the efficacy. The secondary outcomes were used to assess the safety. Statistics This study was designed to explore the efficacy and safety of PS inhalation via VMN compared with LISA for RDS treatment as assessed by the need for MVET within 72 hours after the initiation of NCPPV treatment. Since this study was an exploratory study, the goal of sample size estimation was to ensure a sufficient probability of observing a lower incidence rate of MVET in the VMN group than in the LISA group rather than to achieve specific statistical power for the superiority test. We assumed incidence rates of MVET of 10% for the VMN group and 20% for the LISA group. Under this assumption, a sample size of 25 neonates per group would provide an 84.1% probability of observing a lower MVET incidence rate in the VMN group than in the LISA group. The analyses were performed using SPSS version 26.0 (IBM). For continuous variables, t tests and Mann‒Whitney U tests were used for normally distributed and skewed variables, respectively. An analysis of covariance (ANCOVA) model was used to analyze the differences in blood gas levels between the two groups. The χ 2 test or Fisher test was performed to compare binary outcomes. Odds ratio and 95% confidence intervals (CI) were calculated. A 2-sided P < 0.05 was considered to indicate statistical significance. Results A total of 124 premature infants were screened. 56 were excluded, 51 met at least 1 exclusion criterion and 5 were transferred to other hospitals. From the remaining 68 premature infants, 13 parents refused to participate in our study, and 6 parents withdrew consent. Thus, 49 were randomized. 24 premature infants were randomized to the LISA group, and 25 infants were randomized to the VMN group (Figure). The 2 groups were balanced in terms of baseline characteristics. Gestational age, birth weight, sex, Apgar scores at 1 and 5 minutes, maternal age, and prenatal corticosteroid prophylaxis were similar between the VMN group and the LISA group (Table 1). Table 1. Comparision of Baseline Characteristics No. (%) Variable VMN Group (n=25) LISA Group (n=24) Gestation age, mean (SD),wk 30.4 (1.5) 29.6 (1.64) Birth weight, mean(SD), g 1343 (124.69) 1364.37 (139.04) Male 14 (56) 15 (62.5) Apgar 1 min, median (IQR)a 7 (6,7) 7 (6,7) Apgar 5 min, median (IQR)a 8 (8,9) 8 (8,9) Maternal age, mean (SD) 31.6 (4.99) 30.7 (4.02) Prenatal corticosteroid prophylaxis 17 (68) 17 (70.8) Abbreviations: IQR, interquartile range; VMN, vibrating mesh nebulizer; LISA, less invasive surfactant administration. a Scores range from 0 to 10, with higher scores indicating greater physical well-being of newborn. The difference (VMN group - LISA group) in pH was 0.04 (95% CI, -0.02 to 0.09; P =0.174), the difference in PaO 2 /FiO 2 was 27.16 (95% CI, -13.40 to 67.73; P =0.184), and the difference in PaCO 2 was -1.16 (95% CI, -6.84 to 4.52; P =0.684) (Table 2). Table 2. Differences in PS Dosage and Blood Gas Analysis Between Groups Outcomes Mean (95%CI) P value VMN Group (n=25) LISA Group (n=24) Difference pH 7.34(7.30-7.37) 7.30 (7.26-7.34) 0.04 (-0.02 to 0.09) 0.174 PaO 2 /FiO 2 246.45(219.62-273.28) 219.28 (191.83-246.73) 27.16 (-13.40 to 67.73) 0.184 PaCO 2 46.08(42.11-50.06) 47.24 (43.18-51.30) -1.16 (-6.84 to 4.52) 0.684 Abbreviations: PS, pulmonary surfactant; CI, confidence intervals; VMN, vibrating mesh nebulizer; LISA, less invasive surfactant administration. The need for MVET within 72 hours was lower in the VMN group than in the LISA group, but the difference was not significant (3 [12%] vs. 5 [20.8%]; odds ratio, 0.52; 95% CI, 0.11–2.46; P = 0.653). The incidence of BPD was lower in the VMN group than in the LISA group (4 [16%] vs. 6 [25%]; odds ratio, 0.57; 95% CI, 0.11–2.34; P = 0.669). In addition, there was one death in the LISA group. The incidences of AoP (2[8%] vs. 10[41.67%]; odds ratio, 0.10; 95%CI, 0.02-0.537; P =0.003), arrhythmia (2[8%] vs. 18[75%]; odds ratio, 0.03; 95%CI, 0.005–0.161; P <0.001), and oxygen saturation <85% (3[12%] vs. 16[66.67%]; odds ratio, 0.07; 95%CI, 0.02–0.298; P <0.001) were significantly different between the two groups. There was no difference in the pneumothorax, PVL, ROP, NEC, PVH-IVH, and application of PS again between the two groups (Table 3). Table 3. Comparison of Outcomes Variable VMN Group (n=25) LISA Group (n=24) Odd ratio (95%CI) P value Primary outcomes, No (%) MVET 3(12) 5(20.8) 0.52(0.11-2.46) 0.653 BPD 4(16) 6(25) 0.57(0.12-2.34) 0.669 Death in hospital 0(0) 1(4.17) - 0.490 Secondary outcomes, No (%) AoP 2(8) 10(41.67) 0.10(0.02-0.537) 0.003 Arrhythmia 2(8) 18(75) 0.03(0.005-0.161) <0.001 Oxygen saturation <85% 3(12) 16(66.67) 0.07(0.02-0.298) <0.001 Pneumothorax 0(0) 0(0) - - PVL 2(8) 2(8.33) 0.96(0.12-7.40) 1.000 ROP 6(24) 5(20.8) 1.2(0.31-4.61) 0.791 NEC 1(4) 2(8.33) 0.46(0.04-5.41) 0.971 PVH-IVH 6(24) 6(25) 0.95(0.26-3.48) 0.935 Application of PS again 1(4) 1(4.17) 0.96(0.06-16.24) 1.000 Abbreviations: VMN, vibrating mesh nebulizer; LISA, less invasive surfactant administration; CI, confidence intervals; MVET, mechanical ventilation through an endotracheal tube; BPD, bronchopulmonary dysplasia; AoP, apnoea of prematurity; PS, pulmonary surfactant; PVL, periventricular leukomalacia; ROP, retinopathy of prematurity; NEC, necrotizing enterocolitis; PVH-IVH, periventricular or intraventricular hemorrhage. Discussion In this multicenter clinical trial, we randomized 49 premature infants with RDS born at less than 32 weeks of gestation and weighing less than 1500 g to either the VMN group or LISA group. Our study indicated that VMN, as a noninvasive technique, would produce safety for the treatment of RDS in premature neonates. Although there was no statistical difference between VMN and LISA in efficacy, to our knowledge, this study was the first RCT in premature infants with RDS to compare the therapeutic effects of VMN and LISA. However, this was an exploratory study. A powered RCT is needed to provide strong evidence on whether VMN could replace LISA for the treatment of neonatal RDS. The benefits of LISA in the treatment of RDS have been extensively studied. Previous clinical trials have demonstrated the critical role of LISA in premature infants with RDS. LISA can increase the risk of BPD or death and the duration of mechanical ventilation. 8 The disadvantages of LISA cannot be ignored. Potential complications of catheter insertion during laryngoscopy include cough, arrhythmias, PS reflux, increased intracranial pressure, prolonged hypoxemia and pain. 9 In addition, a multidisciplinary team is important and necessary to perform LISA in critically ill preterm infants. 10 Thus, the therapeutic effect of the complex LISA procedure is determined by multiple factors. A noninvasive modality with a simple procedure and the same therapeutic benefits as LISA is worthy of investigation. The VMN is an innovative technology for the treatment of respiratory diseases. In our study, the nebulizer component of the VMN was made of palladium alloy mesh with 1,000 uniformly distributed holes with a diameter of 5 μm. This mesh produces nebulized particles of 1–5 μm via high-frequency vibration, producing a low-velocity aerosol that reaches the end of the bronchus and the alveoli. 11 Compared with a jet nebulizer, the VMN avoids altering the properties of the PS and does not generate excessive heat or flow that could injure the lungs. 12 Thus, the VMN maximizes the delivery of a fine mist of PS to the deep tissues of the lung while preserving the integrity of the PS, resulting in truly noninvasive treatment. Because of its noninvasive nature, determining the role of the VMN in the treatment of premature infants with RDS is an attractive area of research. In the study by Minocchieri et al. of 64 premature infants with RDS, 34.37% (11 of 32) of patients treated with VMN and CPAP were intubated, whereas 68.75% (22 of 32) of patients treated with CPAP alone were intubated. There was no evidence of BPD in either group. 13 Dani C and colleagues reported that in the groups receiving PS 200 mg/kg and PS 400 mg/kg administered via VMN, the incidence of MVET within 72 hours was 57% (24 of 42 infants) and 49% (20 of 41 infants), respectively. However, compared with CPAP ventilation, the VMN approach was not associated with a lower risk of intubation. 14 Currently, reports on the differences between VMN and LISA in the treatment of RDS in preterm infants are rare. We explored treatment differences between VMN and LISA in a small-sized prospective clinical trial. In the absence of similar studies, we compared our results with those of previous LISA studies to carefully interpret the advantages and disadvantages of VMN for RDS. Previous RCTs of the LISA procedure reported that the incidence of MVET within 72 hours varies from 10% to 40%, 6, 15-23 and the incidence of BPD ranges from 6% to 31%. 15-19, 24, 25 In our study, the incidences of MVET and BPD in our LISA group were 20.8% and 25%, respectively. Our results were similar to those found in the previous RCTs of LISA. In addition, the incidence rates of MVET within 72 hours and BPD in our VMN group were 12% and 16%, respectively. Compared with LISA, although there is no statistical difference, these lower incidence rates are promising and merit further clinical trials to explore the therapeutic value of VMN as an alternative to LISA in premature infants with RDS. In our study, the complications of LISA procedures, such as AoP, arrhythmias, and transient decrease in oxygen saturation, were common. Interestingly, VMN was associated with a lower incidence of these complications. In our opinion, this finding was due to the characteristics of the truly non-invasive approach of VMNs. It suggested that VMN could be safer than LISA, although there was no difference in efficacy between the two approaches based on our arterial blood gas analysis and primary outcomes. Limitations This study has several limitations to acknowledge. First, this trial was not blinded. As an open-label RCT, participants and outcome assessors were aware of the intervention for the premature infants. This could introduce biases and reduce the internal validity of the study. Second, as an exploratory study, the analysed results are based on a small sample size. This means that the efficacy and feasibility of VMN cannot be fully assessed. Conclusion The findings of this multicenter, open-label, exploratory, randomized clinical trial revealed that compared with LISA, the noninvasive technique of VMN can be a safe method for delivering PS to preterm infants with RDS without significant adverse effects. However, there was no difference between VMN and LISA in the efficacy of neonate RDS. Whether VMN can replace LISA in treating RDS or not, further powered RCTs are needed. Declarations Author Affiliations The First Affiliated Hospital of Bengbu Medical University, Bengbu, Anhui, China (Jiang, Chen, Li); Huaibei Maternal and Child Health Hospital, Huaibei, Anhui, China (Wang, Wang); Linquan County People's Hospital, Fuyang, Anhui, China (Guo, Li); The Hospital of Suixi County, Huaibei, Anhui, China (Li, Wang). Suzhou municipal Hospital, Suzhou, Anhui, China (Xu, Zou); Leshan Women and Children's Hospital, Leshan, Sichuan, China (Wan); the People's hospital of Leshan, Leshan, Sichuan, China (Rao). Author Contributions: Dr Xin Chen had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Concept and design: Yiyao Jiang, Xin Chen. Acquisition, analysis, or interpretation of data: Yiyao Jiang, Xin Chen, Runa Li. Drafting of the manuscript: Yiyao Jiang. Critical revision of the manuscript for important intellectual content: All authors. Statistical analysis: Yiyao Jiang. Obtained funding: Yiyao Jiang, Xin Chen. Administrative, technical, or material support: Xin Chen. Supervision: Xin Chen. Acknowledgements We purchased VMN from Aerogen Co., Ltd. (Ireland). We did not receive any financial support from Aerogen Co., Ltd. The company had no role in the analysis of the data or the decision to submit the results for publication. Conflict of Interest Disclosures: None. Funding: The study was funded by the Natural Science Research Project of Anhui Educational Committee (2024AH051191), Innovation Project of Bengbu Science and Technology Bureau (2024ZD0021), Natural Science Foundation of Bengbu Medical College (2022byflc009, 2022byzd030), and Science Foundation for Outstanding Youth of the First Affiliated Hospital of Bengbu Medical College (2021byyfyjq02). Role of the Funder/Sponsor The funder had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. References Avery ME, Mead J (1959) Surface properties in relation to atelectasis and hyaline membrane disease. AMA J Dis Child. ;97(5, pt 1):517–523. 10.1001/archpedi.1959.02070010519001 Pramanik AK, Rangaswamy N, Gates T (2015) Neonatal respiratory distress: a practical approach to its diagnosis and management. 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Chen","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAu0lEQVRIiWNgGAWjYBACxobzHx9+qKiR4ydaC3PjAWNjiTPHjCUbiNXC3nzATIK3jTlxwwFitfC2HUg2kGxjS9x8PHkDw4+KbYS1SPYcOPig4JyM8bYzzwoYe87cJqzFcMbBZgOJMjbZbTdyDJgZ24jQYn//MZsEDxsz4+YZxGphbDgG1NLGrLhBgngtZ5jBgSwB9MtBovwC1MIIicr25I0PflQQoQUJJBgcIEk9WAupOkbBKBgFo2CEAAB1cULnCMg93wAAAABJRU5ErkJggg==","orcid":"","institution":"The First Affiliated Hospital of Bengbu Medical University","correspondingAuthor":true,"prefix":"","firstName":"Xin","middleName":"","lastName":"Chen","suffix":""},{"id":451691687,"identity":"5d088e99-db96-4fe7-a440-f044664de280","order_by":2,"name":"Runa Li","email":"","orcid":"","institution":"The First Affiliated Hospital of Bengbu Medical University","correspondingAuthor":false,"prefix":"","firstName":"Runa","middleName":"","lastName":"Li","suffix":""},{"id":451691688,"identity":"79cdc9c6-e3ad-478d-bdb4-4b05b051ba7c","order_by":3,"name":"Hui Wang","email":"","orcid":"","institution":"Huaibei Maternal and Child Health Hospital","correspondingAuthor":false,"prefix":"","firstName":"Hui","middleName":"","lastName":"Wang","suffix":""},{"id":451691689,"identity":"272fa413-7aa4-447c-9c2a-30d58e949379","order_by":4,"name":"Hanqing Wang","email":"","orcid":"","institution":"Huaibei Maternal and Child Health Hospital","correspondingAuthor":false,"prefix":"","firstName":"Hanqing","middleName":"","lastName":"Wang","suffix":""},{"id":451691690,"identity":"d4ef2675-9fa2-4a32-8de2-6dc9c7e39839","order_by":5,"name":"Qian Guo","email":"","orcid":"","institution":"Linquan County People's Hospital","correspondingAuthor":false,"prefix":"","firstName":"Qian","middleName":"","lastName":"Guo","suffix":""},{"id":451691692,"identity":"1044451d-631a-4c8b-acb8-eef62f14aec9","order_by":6,"name":"Jinhong Li","email":"","orcid":"","institution":"Linquan County People's Hospital","correspondingAuthor":false,"prefix":"","firstName":"Jinhong","middleName":"","lastName":"Li","suffix":""},{"id":451691694,"identity":"7fa59525-e2bd-40a2-b682-c1c043524850","order_by":7,"name":"Dexin Li","email":"","orcid":"","institution":"The Hospital of Suixi County","correspondingAuthor":false,"prefix":"","firstName":"Dexin","middleName":"","lastName":"Li","suffix":""},{"id":451691699,"identity":"f403ef5a-0958-4d2e-8bde-7233cf1ccfdc","order_by":8,"name":"Bo Wang","email":"","orcid":"","institution":"The Hospital of Suixi County","correspondingAuthor":false,"prefix":"","firstName":"Bo","middleName":"","lastName":"Wang","suffix":""},{"id":451691701,"identity":"c867ff4a-9793-4779-aafe-ebe15f512e61","order_by":9,"name":"Hong Xu","email":"","orcid":"","institution":"Suzhou municipal Hospital","correspondingAuthor":false,"prefix":"","firstName":"Hong","middleName":"","lastName":"Xu","suffix":""},{"id":451691702,"identity":"bb7c2fef-f120-4d49-a336-32fd11068ec1","order_by":10,"name":"Qiaoqiao Zou","email":"","orcid":"","institution":"Suzhou municipal Hospital","correspondingAuthor":false,"prefix":"","firstName":"Qiaoqiao","middleName":"","lastName":"Zou","suffix":""},{"id":451691703,"identity":"731384ed-06b5-4793-8995-4a045ce9531e","order_by":11,"name":"Hong Wan","email":"","orcid":"","institution":"Leshan Women and Children's Hospital","correspondingAuthor":false,"prefix":"","firstName":"Hong","middleName":"","lastName":"Wan","suffix":""},{"id":451691704,"identity":"5eed0ece-2b8f-426f-8c0d-d933d7b29c77","order_by":12,"name":"Rui Rao","email":"","orcid":"","institution":"the People's hospital of Leshan","correspondingAuthor":false,"prefix":"","firstName":"Rui","middleName":"","lastName":"Rao","suffix":""}],"badges":[],"createdAt":"2025-04-20 08:53:12","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6488329/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6488329/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":82350528,"identity":"ec1b172e-8327-4777-9bce-42a2a3c395e8","added_by":"auto","created_at":"2025-05-09 10:52:44","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":282412,"visible":true,"origin":"","legend":"\u003cp\u003eFlow of Participants in the Study.\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-6488329/v1/1c2fd61bd275c9a7cdb28610.png"},{"id":83763938,"identity":"f7ef4878-19f8-4273-844a-1b117d0e561a","added_by":"auto","created_at":"2025-06-02 10:23:52","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":796933,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6488329/v1/01237db9-d08c-4b3f-89a2-aa2708170eb7.pdf"},{"id":82350536,"identity":"e1fac77e-954b-4720-865f-ef0bbc02088b","added_by":"auto","created_at":"2025-05-09 10:52:45","extension":"doc","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":276480,"visible":true,"origin":"","legend":"","description":"","filename":"protocolandstatisticalanalysisplan3rd.doc","url":"https://assets-eu.researchsquare.com/files/rs-6488329/v1/701b0105e6aabdd276b8de27.doc"}],"financialInterests":"No competing interests reported.","formattedTitle":"Vibrating Mesh Nebulizers vs. Less Invasive Surfactant Administration in the Treatment of Preterm Respiratory Distress Syndrome: A Multicenter, Open-label, Randomized Clinical Trial","fulltext":[{"header":"What is Known","content":"\u003cp\u003eLISA is commonly used for treatment of RDS in preterm neonates.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eVMN has been introduced as a newer approach to deliver PS for the treatment of NRDS.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eWhat is New:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCompared with LISA, the noninvasive technique of VMN can be a safe way for delivering PS to preterm infants with RDS without significant adverse effects.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThere was no difference between VMN and LISA in the efficacy of neonate RDS.\u003c/p\u003e"},{"header":"Introduction","content":"\u003cp\u003eRespiratory distress syndrome (RDS), caused by PS deficiency, is considered a major cause of early mortality and poor long-term prognosis in premature neonates.\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e The incidence of neonatal RDS ranges from 5\u0026ndash;60% in preterm neonates.\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e According to European consensus guidelines on the management of RDS, exogenous PS administration combined with mechanical ventilation can significantly reduce the mortality rate of RDS.\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e The classical route of PS administration involves injection into the lungs via endotracheal intubation. However, this procedure is invasive and can cause adverse effects in premature neonates. Thus, minimally invasive or noninvasive routes of PS delivery continue to be a popular research topic.\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e Innovative strategies such as nasal continuous positive airway pressure (NCPAP) combined with PS delivery techniques, such as intubation-surfactant-extubation (INSURE) and less invasive surfactant administration (LISA), have been widely used to treat RDS.\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e,\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e Although these techniques have reduced the need for mechanical ventilation, these methods are still essentially invasive.\u003c/p\u003e \u003cp\u003eThe use of VMN is a noninvasive way to further optimize PS delivery via inhalation. Compared with INSURE and LISA, VMN forms PS into atomized particles and facilitates PS deposition in the alveoli for the treatment of RDS in premature infants, with theoretically greater advantages. Berlinski comprehensively summarized the characteristics of VMN and their application in children.\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e However, evidence from clinical trials related to the use of VMN for the treatment of RDS in preterm infants is lacking. Therefore, we conducted this multicenter, open-label, randomized clinical trial to explorate the efficacy and safety of PS inhalation via VMN for the treatment of RDS in premature neonates.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy Design\u003c/h2\u003e \u003cp\u003eThis prospective multicenter, open-label, exploratory, RCT was a 2 parallel-group design with a 1:1 allocation ratio and was performed between January 2023 and December 2024. A total of 7 tertiary referral NICUs in China participated in this trial. Ethical review approval was obtained from the medical ethics committees of each of the 7 participating centers, and this study was registered with the Chinese Clinical Trial Registry (ChiCTR2300072262). The study was conducted in accordance with the protocol (Supplement 1) and followed the tenets of the Declaration of Helsinki. Only children whose legal guardians provided written informed consent were enrolled. This manuscript followed the Consolidated Standards of Reporting Trials (CONSORT) guidelines.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eStudy Population\u003c/h3\u003e\n\u003cp\u003eAttending neonatologists screened the neonates daily for eligibility. The inclusion criteria were as follows: (1) gestational age between 25 and 32 weeks; (2) weight less than 1500 g; (3) gradually aggravated dyspnea after birth that met the diagnostic criteria for neonatal RDS as assessed by chest radiography; and (4) the need for noninvasive ventilatory support as initial treatment after birth. Neonates were excluded if they had one of the following conditions: (1) lack of effective spontaneous breathing; (2) indications for invasive ventilation, including fraction of inspired oxygen (FiO\u003csub\u003e2\u003c/sub\u003e)\u0026thinsp;\u0026gt;\u0026thinsp;0.4, arterial partial pressure of oxygen (PaO\u003csub\u003e2\u003c/sub\u003e)\u0026thinsp;\u0026lt;\u0026thinsp;50 mmHg, and/or arterial partial pressure of carbon dioxide (PaCO\u003csub\u003e2\u003c/sub\u003e)\u0026thinsp;\u0026gt;\u0026thinsp;65 mmHg and pH\u0026thinsp;\u0026lt;\u0026thinsp;7.25; (3) major congenital anomalies or chromosomal abnormalities; (4) neuromuscular diseases; or (5) suspected congenital lung diseases, malformations, or pulmonary hypoplasia.\u003c/p\u003e\n\u003ch3\u003eIntervention\u003c/h3\u003e\n\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eVMN Group\u003c/h2\u003e \u003cp\u003eThe VMN was purchased from Aerogen Co., Ltd. (Ireland). Premature neonates were placed in the supine position to keep the airway open. While the infant was breathing via NCPAP ventilation, the VMN was connected to the inhalation tube of the ventilator via a T-tube. The VMN controller was connected to a nebulizing device. PS was injected into the container of the nebulizing device. Then, the controller was turned on, and nebulized aerosols were produced. If the drug became viscous or stagnant during nebulization, it was diluted with an appropriate amount of sterilized water for injection to complete nebulization.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eLISA Group\u003c/h3\u003e\n\u003cp\u003eNeonatologists and nurses at each hospital received training to ensure the homogeneity and safety of the LISA technique. While the infant was on NCPAP ventilation, a 6 Fr feeding tube was placed in the trachea via direct laryngoscopy with Magill forceps. The distance (cm) from the end of the feeding tube to the infant's mouth was calculated as follows: weight (kg)\u0026thinsp;+\u0026thinsp;6. Once the correct position was confirmed, the tube was fixed to the upper jaw of the infant, and slow and continuous PS delivery was initiated. The tube was removed after PS delivery.\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003ePS dosage and the Criterion of re-intubation\u003c/h2\u003e \u003cp\u003eIn both groups, the dosage of PS (Chiesi Pharmaceutical Co., Ltd, Italy) was 200 mg/kg. Arterial blood gas levels were measured before and 30 minutes after PS delivery, and the changes in these levels were calculated. The re-intubation criteria were as follows: (1) recurrent apnoea\u0026thinsp;\u0026gt;\u0026thinsp;3 times per hour and heart rate\u0026thinsp;\u0026lt;\u0026thinsp;100 rpm; (2) there was only 1 apnoea in 24 hours that was not relieved by caffeine treatment; (3) FiO\u003csub\u003e2\u003c/sub\u003e\u0026thinsp;\u0026gt;\u0026thinsp;0.4 and PaO\u003csub\u003e2\u003c/sub\u003e\u0026thinsp;\u0026lt;\u0026thinsp;50mmHg; (4) PaCO\u003csub\u003e2\u003c/sub\u003e\u0026thinsp;\u0026gt;\u0026thinsp;60mmHg and pH\u0026thinsp;\u0026lt;\u0026thinsp;7.20; (5) contraindications to non-invasive ventilation such as pulmonary haemorrhage, severe arrhythmia, shock, frequent convulsions, neonatal NEC, intestinal obstruction, etc.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eRandomization\u003c/h3\u003e\n\u003cp\u003eEligible premature neonates were randomized (1:1) to either the VMN group or the LISA group. The randomization code was generated via a web-based computer-generated randomization tool (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.randomizer.org\u003c/span\u003e\u003cspan address=\"https://www.randomizer.org\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e). An independent statistician prepared the randomization schedule in permuted blocks of 2, 4 or 6. The group assignments were placed in sequentially numbered, sealed, opaque envelopes that were opened only after consent was obtained from the parents.\u003c/p\u003e\n\u003ch3\u003eAssessments\u003c/h3\u003e\n\u003cp\u003eArterial blood gas analysis results, including pH, PaCO\u003csub\u003e2\u003c/sub\u003e, and PaO\u003csub\u003e2\u003c/sub\u003e/FiO\u003csub\u003e2\u003c/sub\u003e, were compared between VMN group and LISA group. The primary outcomes were (1) the need for MVET within 72 hours after the initiation of NCPPV treatment, (2) the occurrence of bronchopulmonary dysplasia (BPD), and (3) death in the hospital. The secondary outcomes included apnoea of prematurity (AoP), arrhythmia, oxygen saturation\u0026thinsp;\u0026lt;\u0026thinsp;85%, pneumothorax, periventricular leukomalacia (PVL), retinopathy of prematurity (ROP), necrotizing enterocolitis (NEC), periventricular or intraventricular hemorrhage (PVH-IVH), and the reapplication of PS. For the two groups, the arterial blood gas analysis and primary outcomes were used to evaluate the efficacy. The secondary outcomes were used to assess the safety.\u003c/p\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eStatistics\u003c/h2\u003e \u003cp\u003eThis study was designed to explore the efficacy and safety of PS inhalation via VMN compared with LISA for RDS treatment as assessed by the need for MVET within 72 hours after the initiation of NCPPV treatment. Since this study was an exploratory study, the goal of sample size estimation was to ensure a sufficient probability of observing a lower incidence rate of MVET in the VMN group than in the LISA group rather than to achieve specific statistical power for the superiority test. We assumed incidence rates of MVET of 10% for the VMN group and 20% for the LISA group. Under this assumption, a sample size of 25 neonates per group would provide an 84.1% probability of observing a lower MVET incidence rate in the VMN group than in the LISA group.\u003c/p\u003e \u003cp\u003eThe analyses were performed using SPSS version 26.0 (IBM). For continuous variables, \u003cem\u003et\u003c/em\u003e tests and Mann‒Whitney U tests were used for normally distributed and skewed variables, respectively. An analysis of covariance (ANCOVA) model was used to analyze the differences in blood gas levels between the two groups. The χ\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e test or Fisher test was performed to compare binary outcomes. Odds ratio and 95% confidence intervals (CI) were calculated. A 2-sided \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered to indicate statistical significance.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eA total of 124 premature infants were screened. 56 were excluded, 51 met at least 1 exclusion criterion and 5 were transferred to other hospitals. From the remaining 68 premature infants, 13 parents refused to participate in our study, and 6 parents withdrew consent. Thus, 49 were randomized. 24 premature infants were randomized to the LISA group, and 25 infants were randomized to the VMN group (Figure). The 2 groups were balanced in terms of baseline characteristics. Gestational age, birth weight, sex, Apgar scores at 1 and 5 minutes, maternal age, and prenatal corticosteroid prophylaxis were similar between the VMN group and the LISA group (Table\u0026nbsp;1).\u003c/p\u003e\u003cp\u003eTable\u0026nbsp;1. Comparision of\u0026nbsp;Baseline Characteristics\u003c/p\u003e\n\u003cdiv\u003e\n \u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"568\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"3\" valign=\"top\" style=\"width: 568px;\"\u003e\n \u003cp\u003eNo.\u0026nbsp;(%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 244px;\"\u003e\n \u003cp\u003eVariable\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 159px;\"\u003e\n \u003cp\u003eVMN Group\u003c/p\u003e\n \u003cp\u003e(n=25)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 165px;\"\u003e\n \u003cp\u003eLISA Group\u003c/p\u003e\n \u003cp\u003e(n=24)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 244px;\"\u003e\n \u003cp\u003eGestation\u0026nbsp;age,\u0026nbsp;mean\u0026nbsp;(SD),wk\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 159px;\"\u003e\n \u003cp\u003e30.4\u0026nbsp;(1.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 165px;\"\u003e\n \u003cp\u003e29.6\u0026nbsp;(1.64)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 244px;\"\u003e\n \u003cp\u003eBirth weight, mean(SD), g\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 159px;\"\u003e\n \u003cp\u003e1343 (124.69)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 165px;\"\u003e\n \u003cp\u003e1364.37 (139.04)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 244px;\"\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 159px;\"\u003e\n \u003cp\u003e14\u0026nbsp;(56)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 165px;\"\u003e\n \u003cp\u003e15\u0026nbsp;(62.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 244px;\"\u003e\n \u003cp\u003eApgar\u0026nbsp;1 min, median (IQR)a\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 159px;\"\u003e\n \u003cp\u003e7\u0026nbsp;(6,7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 165px;\"\u003e\n \u003cp\u003e7\u0026nbsp;(6,7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 244px;\"\u003e\n \u003cp\u003eApgar 5 min, median\u0026nbsp;(IQR)a\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 159px;\"\u003e\n \u003cp\u003e8\u0026nbsp;(8,9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 165px;\"\u003e\n \u003cp\u003e8\u0026nbsp;(8,9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 244px;\"\u003e\n \u003cp\u003eMaternal age, mean\u0026nbsp;(SD)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 159px;\"\u003e\n \u003cp\u003e31.6\u0026nbsp;(4.99)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 165px;\"\u003e\n \u003cp\u003e30.7\u0026nbsp;(4.02)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 244px;\"\u003e\n \u003cp\u003ePrenatal corticosteroid prophylaxis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 159px;\"\u003e\n \u003cp\u003e17\u0026nbsp;(68)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 165px;\"\u003e\n \u003cp\u003e17\u0026nbsp;(70.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003eAbbreviations: IQR, interquartile range; VMN, vibrating mesh nebulizer; LISA, less invasive surfactant administration. a Scores range from 0 to 10, with higher scores indicating greater physical well-being of newborn.\u003c/p\u003e\n\u003cp\u003eThe difference (VMN group - LISA group) in pH was 0.04 (95% CI, -0.02 to 0.09; \u003cem\u003eP\u003c/em\u003e =0.174), the difference in PaO\u003csub\u003e2\u003c/sub\u003e/FiO\u003csub\u003e2\u003c/sub\u003e was 27.16 (95% CI, -13.40 to 67.73; \u003cem\u003eP\u003c/em\u003e =0.184), and the difference in PaCO\u003csub\u003e2\u003c/sub\u003e was -1.16 (95% CI, -6.84 to 4.52; \u003cem\u003eP\u003c/em\u003e =0.684) (Table 2).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTable 2. Differences in PS Dosage and Blood Gas Analysis Between Groups\u003c/p\u003e\n\u003cdiv\u003e\n \u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" class=\"fr-table-selection-hover\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" style=\"width: 112px;\"\u003e\n \u003cp\u003eOutcomes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" style=\"width: 654px;\"\u003e\n \u003cp\u003eMean (95%CI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 86px;\"\u003e\n \u003cp\u003e\u003cem\u003eP\u0026nbsp;\u003c/em\u003evalue\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 219px;\"\u003e\n \u003cp\u003eVMN Group\u0026nbsp;(n=25)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 204px;\"\u003e\n \u003cp\u003eLISA Group\u0026nbsp;(n=24)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 231px;\"\u003e\n \u003cp\u003eDifference\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 112px;\"\u003e\n \u003cp\u003epH\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 219px;\"\u003e\n \u003cp\u003e7.34(7.30-7.37)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 204px;\"\u003e\n \u003cp\u003e7.30 (7.26-7.34)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 231px;\"\u003e\n \u003cp\u003e0.04 (-0.02 to 0.09)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 86px;\"\u003e\n \u003cp\u003e0.174\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 112px;\"\u003e\n \u003cp\u003ePaO\u003csub\u003e2\u003c/sub\u003e/FiO\u003csub\u003e2\u003c/sub\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 219px;\"\u003e\n \u003cp\u003e246.45(219.62-273.28)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 204px;\"\u003e\n \u003cp\u003e219.28 (191.83-246.73)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 231px;\"\u003e\n \u003cp\u003e27.16 (-13.40 to 67.73)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 86px;\"\u003e\n \u003cp\u003e0.184\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 112px;\"\u003e\n \u003cp\u003ePaCO\u003csub\u003e2\u003c/sub\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 219px;\"\u003e\n \u003cp\u003e46.08(42.11-50.06)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 204px;\"\u003e\n \u003cp\u003e47.24 (43.18-51.30)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 231px;\"\u003e\n \u003cp\u003e-1.16 (-6.84 to 4.52)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 86px;\"\u003e\n \u003cp\u003e0.684\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003eAbbreviations: PS, pulmonary surfactant; CI, confidence intervals; VMN, vibrating mesh nebulizer; LISA, less invasive surfactant administration.\u003c/p\u003e\n\u003cp\u003eThe need for MVET within 72 hours was lower in the VMN group than in the LISA group, but the difference was not significant (3 [12%] vs. 5 [20.8%]; odds ratio, 0.52; 95% CI, 0.11\u0026ndash;2.46; \u003cem\u003eP\u003c/em\u003e= 0.653). The incidence of BPD was lower in the VMN group than in the LISA group (4 [16%] vs. 6 [25%]; odds ratio, 0.57; 95% CI, 0.11\u0026ndash;2.34; \u003cem\u003eP\u003c/em\u003e= 0.669). In addition, there was one death in the LISA group.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe incidences of AoP (2[8%] vs. 10[41.67%]; odds ratio, 0.10; 95%CI, 0.02-0.537; \u003cem\u003eP\u003c/em\u003e=0.003), arrhythmia (2[8%] vs. 18[75%]; odds ratio, 0.03; 95%CI, 0.005\u0026ndash;0.161; \u003cem\u003eP\u003c/em\u003e\u0026lt;0.001), and oxygen saturation \u0026lt;85% (3[12%] vs. 16[66.67%]; odds ratio, 0.07; 95%CI, 0.02\u0026ndash;0.298; \u003cem\u003eP\u003c/em\u003e\u0026lt;0.001) were significantly different between the two groups. There was no difference in the pneumothorax, PVL, ROP, NEC, PVH-IVH, and application of PS again between the two groups (Table 3).\u003c/p\u003e\n\u003cp\u003eTable 3. Comparison of Outcomes\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 199px;\"\u003e\n \u003cp\u003eVariable\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 116px;\"\u003e\n \u003cp\u003eVMN Group\u003c/p\u003e\n \u003cp\u003e(n=25)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 107px;\"\u003e\n \u003cp\u003eLISA Group\u003c/p\u003e\n \u003cp\u003e(n=24)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 145px;\"\u003e\n \u003cp\u003eOdd ratio (95%CI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 135px;\"\u003e\n \u003cp\u003e\u003cem\u003eP\u0026nbsp;\u003c/em\u003evalue\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"5\" style=\"width: 702px;\"\u003e\n \u003cp\u003ePrimary outcomes, No (%)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 199px;\"\u003e\n \u003cp\u003eMVET\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 116px;\"\u003e\n \u003cp\u003e3(12)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 107px;\"\u003e\n \u003cp\u003e5(20.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 145px;\"\u003e\n \u003cp\u003e0.52(0.11-2.46)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 135px;\"\u003e\n \u003cp\u003e0.653\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 199px;\"\u003e\n \u003cp\u003eBPD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 116px;\"\u003e\n \u003cp\u003e4(16)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 107px;\"\u003e\n \u003cp\u003e6(25)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 145px;\"\u003e\n \u003cp\u003e0.57(0.12-2.34)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 135px;\"\u003e\n \u003cp\u003e0.669\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 199px;\"\u003e\n \u003cp\u003eDeath in hospital\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 116px;\"\u003e\n \u003cp\u003e0(0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 107px;\"\u003e\n \u003cp\u003e1(4.17)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 145px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 135px;\"\u003e\n \u003cp\u003e0.490\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"5\" style=\"width: 702px;\"\u003e\n \u003cp\u003eSecondary outcomes, No (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 199px;\"\u003e\n \u003cp\u003eAoP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 116px;\"\u003e\n \u003cp\u003e2(8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 107px;\"\u003e\n \u003cp\u003e10(41.67)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 145px;\"\u003e\n \u003cp\u003e0.10(0.02-0.537)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 135px;\"\u003e\n \u003cp\u003e0.003\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 199px;\"\u003e\n \u003cp\u003eArrhythmia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 116px;\"\u003e\n \u003cp\u003e2(8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 107px;\"\u003e\n \u003cp\u003e18(75)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 145px;\"\u003e\n \u003cp\u003e0.03(0.005-0.161)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 135px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 199px;\"\u003e\n \u003cp\u003eOxygen\u0026nbsp;saturation \u0026lt;85%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 116px;\"\u003e\n \u003cp\u003e3(12)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 107px;\"\u003e\n \u003cp\u003e16(66.67)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 145px;\"\u003e\n \u003cp\u003e0.07(0.02-0.298)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 135px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 199px;\"\u003e\n \u003cp\u003ePneumothorax\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 116px;\"\u003e\n \u003cp\u003e0(0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 107px;\"\u003e\n \u003cp\u003e0(0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 145px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 135px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 199px;\"\u003e\n \u003cp\u003ePVL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 116px;\"\u003e\n \u003cp\u003e2(8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 107px;\"\u003e\n \u003cp\u003e2(8.33)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 145px;\"\u003e\n \u003cp\u003e0.96(0.12-7.40)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 135px;\"\u003e\n \u003cp\u003e1.000\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 199px;\"\u003e\n \u003cp\u003eROP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 116px;\"\u003e\n \u003cp\u003e6(24)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 107px;\"\u003e\n \u003cp\u003e5(20.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 145px;\"\u003e\n \u003cp\u003e1.2(0.31-4.61)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 135px;\"\u003e\n \u003cp\u003e0.791\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 199px;\"\u003e\n \u003cp\u003eNEC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 116px;\"\u003e\n \u003cp\u003e1(4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 107px;\"\u003e\n \u003cp\u003e2(8.33)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 145px;\"\u003e\n \u003cp\u003e0.46(0.04-5.41)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 135px;\"\u003e\n \u003cp\u003e0.971\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 199px;\"\u003e\n \u003cp\u003ePVH-IVH\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 116px;\"\u003e\n \u003cp\u003e6(24)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 107px;\"\u003e\n \u003cp\u003e6(25)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 145px;\"\u003e\n \u003cp\u003e0.95(0.26-3.48)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 135px;\"\u003e\n \u003cp\u003e0.935\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 199px;\"\u003e\n \u003cp\u003eApplication of PS again\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 116px;\"\u003e\n \u003cp\u003e1(4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 107px;\"\u003e\n \u003cp\u003e1(4.17)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 145px;\"\u003e\n \u003cp\u003e0.96(0.06-16.24)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 135px;\"\u003e\n \u003cp\u003e1.000\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eAbbreviations: VMN, vibrating mesh nebulizer; LISA, less invasive surfactant administration; CI, confidence intervals; MVET, mechanical ventilation through an endotracheal tube; BPD, bronchopulmonary dysplasia; AoP, apnoea of prematurity; PS, pulmonary surfactant; PVL, periventricular leukomalacia; ROP, retinopathy of prematurity; NEC, necrotizing enterocolitis; PVH-IVH, periventricular or intraventricular hemorrhage.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this multicenter clinical trial, we randomized 49 premature infants with RDS born at less than 32 weeks of gestation and weighing less than 1500 g to either the VMN group or LISA group. Our study indicated that VMN, as a noninvasive technique, would produce safety for the treatment of RDS in premature neonates. Although there was no statistical difference between VMN and LISA in efficacy, to our knowledge, this study was the first RCT in premature infants with RDS to compare the therapeutic effects of VMN and LISA. However, this was an exploratory study. A powered RCT is needed to provide strong evidence on whether VMN could replace LISA for the treatment of neonatal RDS.\u003c/p\u003e\n\u003cp\u003eThe benefits of LISA in the treatment of RDS have been extensively studied. Previous clinical trials have demonstrated the critical role of LISA in premature infants with RDS. LISA can increase the risk of BPD or death and the duration of mechanical ventilation.\u003csup\u003e8\u003c/sup\u003e The disadvantages of LISA cannot be ignored. Potential complications of catheter insertion during laryngoscopy include cough, arrhythmias, PS reflux, increased intracranial pressure, prolonged hypoxemia and pain.\u003csup\u003e9\u003c/sup\u003e In addition, a multidisciplinary team is important and necessary to perform LISA in critically ill preterm infants.\u003csup\u003e10\u003c/sup\u003e Thus, the therapeutic effect of the complex LISA procedure is determined by multiple factors. A noninvasive modality with a simple procedure and the same therapeutic benefits as LISA is worthy of investigation.\u003c/p\u003e\n\u003cp\u003eThe VMN is an innovative technology for the treatment of respiratory diseases. In our study, the nebulizer component of the VMN was made of palladium alloy mesh with 1,000 uniformly distributed holes with a diameter of 5 \u0026mu;m. This mesh produces nebulized particles of 1\u0026ndash;5 \u0026mu;m via high-frequency vibration, producing a low-velocity aerosol that reaches the end of the bronchus and the alveoli.\u003csup\u003e11\u003c/sup\u003e Compared with a jet nebulizer, the VMN avoids altering the properties of the PS and does not generate excessive heat or flow that could injure the lungs.\u003csup\u003e12\u003c/sup\u003e Thus, the VMN maximizes the delivery of a fine mist of PS to the deep tissues of the lung while preserving the integrity of the PS, resulting in truly noninvasive treatment.\u003c/p\u003e\n\u003cp\u003eBecause of its noninvasive nature, determining the role of the VMN in the treatment of premature infants with RDS is an attractive area of research. In the study by Minocchieri et al. of 64 premature infants with RDS, 34.37% (11 of 32) of patients treated with VMN and CPAP were intubated, whereas 68.75% (22 of 32) of patients treated with CPAP alone were intubated. There was no evidence of BPD in either group.\u003csup\u003e13\u003c/sup\u003e Dani C and colleagues reported that in the groups receiving PS 200 mg/kg and PS 400 mg/kg administered via VMN, the incidence of MVET within 72 hours was 57% (24 of 42 infants) and 49% (20 of 41 infants), respectively. However, compared with CPAP ventilation, the VMN approach was not associated with a lower risk of intubation.\u003csup\u003e14\u003c/sup\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eCurrently, reports on the differences between VMN and LISA in the treatment of RDS in preterm infants are rare. We explored treatment differences between VMN and LISA in a small-sized prospective clinical trial. In the absence of similar studies, we compared our results with those of previous LISA studies to carefully interpret the advantages and disadvantages of VMN for RDS. Previous RCTs of the LISA procedure reported that the incidence of MVET within 72 hours varies from 10% to 40%,\u003csup\u003e6, 15-23\u003c/sup\u003e and the incidence of BPD ranges from 6% to 31%.\u003csup\u003e15-19, 24, 25\u003c/sup\u003e In our study, the incidences of MVET and BPD in our LISA group were 20.8% and 25%, respectively. Our results were similar to those found in the previous RCTs of LISA. In addition, the incidence rates of MVET within 72 hours and BPD in our VMN group were 12% and 16%, respectively. Compared with LISA, although there is no statistical difference, these lower incidence rates are promising and merit further clinical trials to explore the therapeutic value of VMN as an alternative to LISA in premature infants with RDS.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn our study, the complications of LISA procedures, such as AoP, arrhythmias, and transient decrease in oxygen saturation, were common. Interestingly, VMN was associated with a lower incidence of these complications. In our opinion, this finding was due to the characteristics of the truly non-invasive approach of VMNs. It suggested that VMN could be safer than LISA, although there was no difference in efficacy between the two approaches based on our arterial blood gas analysis and primary outcomes.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eLimitations\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study has several limitations to acknowledge. First, this trial was not blinded. As an open-label RCT, participants and outcome assessors were aware of the intervention for the premature infants. This could introduce biases and reduce the internal validity of the study. Second, as an exploratory study, the analysed results are based on a small sample size. This means that the efficacy and feasibility of VMN cannot be fully assessed. \u0026nbsp;\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThe findings of this multicenter, open-label, exploratory, randomized clinical trial revealed that compared with LISA, the noninvasive technique of VMN can be a safe method for delivering PS to preterm infants with RDS without significant adverse effects. However, there was no difference between VMN and LISA in the efficacy of neonate RDS. Whether VMN can replace LISA in treating RDS or not, further powered RCTs are needed.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAuthor Affiliations\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe First Affiliated Hospital of Bengbu Medical University, Bengbu, Anhui, China (Jiang, Chen, Li); Huaibei Maternal and Child Health Hospital, Huaibei, Anhui, China (Wang, Wang); Linquan County People\u0026apos;s Hospital, Fuyang, Anhui, China (Guo, Li); The Hospital of Suixi County, Huaibei, Anhui, China (Li, Wang). Suzhou municipal Hospital, Suzhou, Anhui, China (Xu, Zou); Leshan Women and Children\u0026apos;s Hospital, Leshan, Sichuan, China (Wan); the People\u0026apos;s hospital of Leshan, Leshan, Sichuan, China (Rao).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDr Xin Chen had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Concept and design: Yiyao Jiang, Xin Chen. Acquisition, analysis, or interpretation of data: Yiyao Jiang, Xin Chen, Runa Li. Drafting of the manuscript: Yiyao Jiang. Critical revision of the manuscript for important intellectual content: All authors. Statistical analysis: Yiyao Jiang. Obtained funding: Yiyao Jiang, Xin Chen. Administrative, technical, or material support: Xin Chen. Supervision: Xin Chen.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe purchased VMN from Aerogen Co., Ltd. (Ireland). We did not receive any financial support from Aerogen Co., Ltd. The company had no role in the analysis of the data or the decision to submit the results for publication.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of Interest Disclosures:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNone.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study was funded by the Natural Science Research Project of Anhui Educational Committee (2024AH051191), Innovation Project of Bengbu Science and Technology Bureau (2024ZD0021), Natural Science Foundation of Bengbu Medical College (2022byflc009, 2022byzd030), and Science Foundation for Outstanding Youth of the First Affiliated Hospital of Bengbu Medical College (2021byyfyjq02).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRole of the Funder/Sponsor\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe funder had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eAvery ME, Mead J (1959) Surface properties in relation to atelectasis and hyaline membrane disease. 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JAMA Pediatr 169(8):723\u0026ndash;730. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1001/jamapediatrics.2015.0504\u003c/span\u003e\u003cspan address=\"10.1001/jamapediatrics.2015.0504\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Respiratory distress syndrome, Preterm Infants, Vibrating mesh nebulizers","lastPublishedDoi":"10.21203/rs.3.rs-6488329/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6488329/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eDeficiency of pulmonary surfactant (PS) induces the onset of neonatal respiratory distress syndrome, which can lead to progressively worsening respiratory failure and even death. However, studies on improving lung function via the use of vibrating mesh nebulizer (VMN) technology to deliver PS to premature infants with NRDS are limited. This prospective multicenter, open-label, exploratory, randomized clinical trial, including 2 parallel groups and a 1:1 allocation, was conducted in 7 hospitals from Jan. 1, 2023, to Dec. 31, 2024. Premature infants born at less than 32 weeks of gestation and weighing less than 1500 g who presented after birth with RDS with the need for noninvasive ventilatory support as initial treatment were eligible for inclusion. Of the 49 eligible premature infants, 25 infants were randomized to the VMN group, and 24 infants were randomized to the LISA group. The main objective was to investigate the need for mechanical ventilation via an endotracheal tube (MVET) within 72 hours and the incidence of apnoea of prematurity, arrhythmia, and transient decrease in oxygen saturation. We did not find difference in need of MVET within 72 hours between VMN and LISA group (3 [12%] vs. 5 [20.8%]; odds ratio, 0.52; 95% confidence intervals, 0.11-2.46; \u003cem\u003eP\u003c/em\u003e= 0.653). Comparing the LISA group, the incidence of apnoea of prematurity, arrhythmia, and transient decrease in oxygen saturation was lower in VMN group (all \u003cem\u003eP\u003c/em\u003e \u0026lt;0.05). Conclusion: In this clinical trial, the noninvasive technique of VMN is a feasible and safe method for delivering PS. However, there was no difference between VMN and LISA in the efficacy of neonate RDS. Further RCTs are needed to test whether VMN can replace LISA in the treatment of RDS.\u003c/p\u003e\n\u003cp\u003eTrial registration: ChiCTR2300072262 (https://www.chictr.org.cn), registered on 08/06/2023.\u003c/p\u003e","manuscriptTitle":"Vibrating Mesh Nebulizers vs. Less Invasive Surfactant Administration in the Treatment of Preterm Respiratory Distress Syndrome: A Multicenter, Open-label, Randomized Clinical Trial","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-05-09 10:52:39","doi":"10.21203/rs.3.rs-6488329/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"ebbf7eee-d2fc-45c0-b7db-1654057f4efb","owner":[],"postedDate":"May 9th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-06-02T10:23:27+00:00","versionOfRecord":[],"versionCreatedAt":"2025-05-09 10:52:39","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6488329","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6488329","identity":"rs-6488329","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}