Nasal Continuous Positive Airway Pressure vs Nasal Intermittent Positive Pressure Ventilation in Preterm Infants With Respiratory Distress Syndrome: A Randomized Clinical Trial

Hui Zhang; Yijia Zhang; Lin Zeng; Xiaomei Tong; Meihua Piao; Haiying He; Changliang Zhao; Hua Xie; Zhi Zheng; Qiliang Cui; Yiyu Lai; Huiping Wang; Li Wang; Hongyan Liu; Xiuying Tian; Hui Wu; Lan Kang; Tongyan Han

doi:10.1001/jamanetworkopen.2026.19785

. 2026 Jun 30;9(6):e2619785. doi: 10.1001/jamanetworkopen.2026.19785

Nasal Continuous Positive Airway Pressure vs Nasal Intermittent Positive Pressure Ventilation in Preterm Infants With Respiratory Distress Syndrome

A Randomized Clinical Trial

Hui Zhang ¹, Yijia Zhang ¹, Lin Zeng ², Xiaomei Tong ¹, Meihua Piao ¹, Haiying He ³, Changliang Zhao ³, Hua Xie ⁴, Zhi Zheng ⁵, Qiliang Cui ⁶, Yiyu Lai ⁶, Huiping Wang ⁷, Li Wang ⁸, Hongyan Liu ⁹, Xiuying Tian ¹⁰, Hui Wu ¹¹, Lan Kang ¹², Tongyan Han ^1,^✉

¹Department of Pediatrics, Peking University Third Hospital, Beijing, China

²Research Center of Clinical Epidemiology, Peking University Third Hospital, Beijing, China

³Department of Neonatology, The Third Hospital of Baogang Group, Baotou, China

⁴Department of Neonatology, Affiliated Hospital of Chifeng University, Chifeng, China

⁵Department of Neonatology, Women and Children′s Hospital Affiliated to Xiamen University, Xiamen, China

⁶Department of Neonatology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China

⁷Department of Neonatology, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China

⁸Department of Neonatology, Dalian Women and Children’s Medical Group, Dalian, China

⁹Department of Neonatology, Maternal and Child Health Hospital of Hubei Province, Wuhan, China

¹⁰Department of Neonatology, Tianjin Central Hospital of Gynecology Obstetrics, Tianjin, China

¹¹Department of Neonatology, The First Hospital of Jilin University, Changchun, China

¹²Department of Pediatrics, The Affiliated Hospital of Southwest Medical University, Luzhou, China

Accepted for Publication: April 30, 2026.

Published: June 30, 2026. doi:10.1001/jamanetworkopen.2026.19785

Open Access: This is an open access article distributed under the terms of the CC-BY-NC-ND License, which does not permit alteration or commercial use, including those for text and data mining, AI training, and similar technologies. © 2026 Zhang H et al. JAMA Network Open.

^✉

Corresponding Author: Tongyan Han, MD, Department of Pediatrics, Peking University Third Hospital, 49 North Garden Rd, Haidian District, Beijing 100191, China (tongyanhan@bjmu.edu.cn).

Author Contributions: Drs H. Zhang and Han had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: H. Zhang, Zeng, Cui, Kang, Han.

Acquisition, analysis, or interpretation of data: H. Zhang, Y. Zhang, Tong, Piao, He, Zhao, Xie, Zheng, Cui, Lai, H. Wang, L. Wang, Liu, Tian, Wu, Kang, Han.

Drafting of the manuscript: H. Zhang, Kang.

Critical review of the manuscript for important intellectual content: H. Zhang, Y. Zhang, Zeng, Tong, Piao, He, Zhao, Xie, Zheng, Cui, Lai, H. Wang, L. Wang, Liu, Tian, Wu, Han.

Statistical analysis: H. Zhang, Zeng, Kang.

Obtained funding: H. Zhang, Han.

Administrative, technical, or material support: H. Zhang, He, Zhao, Xie, Zheng, Cui, Lai, H. Wang, L. Wang, Liu, Tian, Han.

Supervision: H. Zhang, Tong, Piao, Wu, Han.

Conflict of Interest Disclosures: None reported.

Funding/Support: The trial was funded by the Clinical Key Program – Innovation Project Category B of Peking University Third Hospital (award No. BYSYZD2022016), the National Key R&D Program of China (award No. 2022YFA1303900), and the Clinical Cohort Construction Program of Peking University Third Hospital (award No. BYSYDL2022010).

Role of the Funder/Sponsor: The funders 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.

Data Sharing Statement: See Supplement 3.

Additional Information: We thank the families of all infants for their participation and dedication, as well as the clinical staff for their care and support.

^✉

Corresponding author.

PMCID: PMC13320649 PMID: 42377961

Key Points

Question

Is nasal continuous positive airway pressure (NCPAP) noninferior to nasal intermittent positive pressure ventilation (NIPPV) as primary support before minimally invasive surfactant administration for reducing intubation within 72 hours in preterm infants with respiratory distress syndrome?

Findings

In this randomized clinical trial of 312 infants, NCPAP was inferior to NIPPV. The incidence of NIV failure within 72 hours was significantly higher in the NCPAP group, leading to early trial termination.

Meaning

These findings suggest that NIPPV may be more effective than NCPAP as primary support for preterm infants with respiratory distress syndrome.

This randomized clinical trial examines whether nasal continuous positive airway pressure (CPAP) is noninferior to nasal intermittent positive pressure ventilation (IPPV) as primary respiratory support for reducing intubation within 72 hours in preterm infants with respiratory distress syndrome.

Abstract

Importance

Respiratory distress syndrome (RDS) remains a leading cause of morbidity and mortality in preterm infants. Evidence regarding the optimal initial noninvasive ventilation (NIV) mode for extremely preterm infants (<30 weeks’ gestation) with RDS is inconsistent.

Objective

To determine whether nasal continuous positive airway pressure (NCPAP) is noninferior to nasal intermittent positive pressure ventilation (NIPPV) as primary respiratory support before minimally invasive surfactant administration (MISA) for reducing intubation within 72 hours in preterm infants with RDS.

Design, Setting, and Participants

This multicenter, noninferiority randomized clinical trial was conducted across 11 tertiary neonatal intensive care units in China from December 2021 to October 2024. The trial was designed to enroll 960 infants but was stopped early after enrolling 312 (32.5% of the target) based on prespecified stopping criteria. The enrolled participants were spontaneously breathing preterm infants at 24 to 29⁺⁶ weeks’ gestation with a diagnosis of RDS requiring noninvasive respiratory support after birth. Data were analyzed from January 7 to May 9, 2025.

Intervention

Infants were randomized 1:1 to receive NCPAP or NIPPV as initial respiratory support. All received MISA within 120 minutes after birth via a 1.67-mm catheter.

Main Outcomes and Measures

The primary outcome was NIV failure, defined as requiring intubation and invasive mechanical ventilation within 72 hours after birth. The noninferiority margin was set at a 10% risk difference. Secondary outcomes included NIV failure within 7 days, surfactant redosing, and major complications (eg, pneumothorax, bronchopulmonary dysplasia).

Results

A total of 312 preterm infants (median [IQR] gestational age, 28.0 [28.6-29.4] weeks; 174 boys [55.8%]) were randomized to the NCPAP group (153 infants) or the NIPPV group (159 infants). NIV failure within 72 hours occurred in 40 infants (26.1%) in the NCPAP group vs 21 infants (13.2%) in the NIPPV group (adjusted risk difference, 12.8%; 95% CI, 4.2%-21.6%; P = .004; O’Brien-Fleming adjusted α = .005), exceeding the noninferiority margin and conclusively demonstrating inferiority of NCPAP. NIV failure within 7 days was also higher in the NCPAP group (42 infants [27.5%] vs 24 infants [15.1%]; risk difference, 12.4%; 95% CI, 3.4%-21.4%; P = .008). No significant differences were observed between groups for most complications.

Conclusions and Relevance

In this randomized clinical trial of preterm infants with RDS, NIPPV with MISA as initial respiratory support significantly reduced NIV failure within 72 hours compared with NCPAP. These findings suggest that NIPPV may be the preferred primary respiratory strategy for this high-risk population, although further evaluation of long-term outcomes is warranted due to early trial termination.

Trial Registration

ClinicalTrials.gov Identifier: NCT05137340

Introduction

Respiratory distress syndrome (RDS) remains a leading cause of morbidity and mortality in preterm infants, particularly those born at less than 30 weeks’ gestation.^1,2 While surfactant replacement therapy remains a cornerstone treatment, evolving delivery strategies aiming to mitigate ventilator-induced lung injury.³ The clinical paradigm has shifted from invasive approaches (intubation, surfactant, and extubation) toward minimally invasive techniques, exemplified by less-invasive surfactant administration (LISA), minimally invasive surfactant therapy (MIST), and minimally invasive surfactant administration (MISA) with specially designed minimally invasive tubes in China.^4,5 These conceptually similar techniques reflect efforts to integrate gentle ventilation into early respiratory management.

Despite advances, debate persists regarding optimal respiratory support after birth.⁶ Current guidelines recommend nasal continuous positive airway pressure (NCPAP) combined with LISA as a first-line strategy to avoid invasive mechanical ventilation (IMV).² However, nasal intermittent positive pressure ventilation (NIPPV), which superimposes intermittent peak pressures on NCPAP, has shown potential benefits in reducing treatment failure in some populations, although evidence for its superiority in extremely preterm infants is inconclusive.^7,8 Importantly, NIPPV is associated with increased risks of abdominal distention, vomiting, and gastrointestinal perforation vs NCPAP,⁹ raising safety concerns.

Meta-analyses confirm NIPPV’ s efficacy in reducing reintubation after extubation compared to NCPAP.¹⁰ However, NIPPV as initial respiratory support with MISA remains unstudied in infants born at less than 30 weeks’ gestation. A multicenter trial in 200 infants with 26 to 32 weeks’ gestation showed that NIPPV with MIST reduced IMV within 72 hours and decreased the incidence of bronchopulmonary dysplasia (BPD), but no significant IMV reduction was observed in its prespecified subgroup of 115 infants with less than 30 week’s gestation.¹¹ This inconsistency underscores the need for rigorous evaluation of NIPPV as primary support with MISA in this highest-risk population.

To address this gap, we conducted a multicenter noninferiority randomized clinical trial comparing NCPAP with NIPPV as primary respiratory support prior to MISA in spontaneously breathing preterm infants (24-29⁺⁶ weeks’ gestation). The trial was halted prematurely after enrolling 312 infants (32.5% of planned 960) when prespecified interim analysis demonstrated conclusive NCPAP inferiority. This report focuses on prespecified 72-hour respiratory outcomes and complications profiles.

Methods

Study Design

This multicenter, noninferiority randomized clinical trial was conducted across 11 tertiary neonatal intensive care units (NICUs) in China. Initially, 14 centers were planned; 3 centers withdrew due to concurrent trials, leaving 11 centers completing the study. The trial protocol was prospectively registered and initially published during the early enrollment phase,¹² with the final trial protocol (including all amendments) and statistical analysis plan provided in Supplement 1. The study protocol was approved by the institutional review boards at all participating centers, and written informed consent was obtained from parents or legal guardians prior to enrollment. A data safety and monitoring committee (DSMC) of 2 independent neonatologists and an independent statistician oversaw trial progress and safety, all external to the participating centers. This study followed the Consolidated Standards of Reporting Trials (CONSORT) reporting guideline.

Inclusion and Exclusion Criteria

Eligible infants were those with gestational age 24 to 29⁺⁶ weeks, with spontaneous breathing at birth, requiring noninvasive respiratory support for respiratory distress, and with an RDS diagnosis within 2 hours after birth (fraction of inspired oxygen [Fio₂] >0.30 to maintain peripheral oxygen saturation [Spo₂] >85%; Silverman Anderson score [SAS] >5 or increase >2 points/h). SAS assesses the degree of respiratory effort by observing and scoring specific physical signs of labored breathing. The score ranges from 0 to 10, with higher scores indicating more severe respiratory distress. Exclusion criteria were intubation prior to surfactant, major congenital anomalies affecting respiration, transfer to other hospitals, parental withdrawal, or participation in other interventional trials.

Randomization

Infants were randomly assigned 1:1 to NCPAP or NIPPV on NICU admission. Randomization was stratified by clinical center, gestational age (24 to 26⁺⁶ weeks, 27 to 29⁺⁶ weeks), birth weight (<1000 g, ≥1000 g), sex, and maternal corticosteroid exposure (complete course, incomplete course, or none). Variable block sizes (4-6) ensured allocation concealment and balance across centers. Treatment allocations were computer generated (R software version X.X [R Project for Statistical Computing) by an independent statistician and concealed in sequentially numbered, sealed opaque envelopes. To minimize allocation bias, multiple-birth infants underwent separate randomization.

Protocol

Preterm infants with spontaneous breathing received standardized noninvasive respiratory support in the delivery room and during NICU admission, using a positive end-expiratory pressure (PEEP) of 6 cm H₂O and Fio₂ 0.40 or less. After NICU admission, infants were randomly assigned to NCPAP or NIPPV. The NCPAP group received continuous pressure via nasal prongs (PEEP, 6-8 cm H₂O; flow rate, 6-12 L/min; Fio₂, 0.21-0.40). The NIPPV group received synchronized ventilation (PEEP, 6-8 cm H₂O; peak inspiratory pressure, 15-20 cm H₂O; inspiratory time, 0.3-0.4 seconds; respiratory rate, 20-40 breaths/min; flow rate, 8-10 L/min; Fio₂, 0.21-0.40). If maximal parameters were insufficient to maintain preductal saturation 90% to 95%, Fio₂ was gradually increased up to 0.40.

Calf pulmonary surfactant (Beijing Double-Crane Pharmaceutical Co. Ltd) was administered via MISA within 120 minutes after birth to infants with RDS receiving NCPAP or NIPPV. A 1.67-mm catheter was inserted 0.5 to 1.0 cm below the vocal cords via direct laryngoscopy, connected to a 5 mL surfactant syringe, and removed after nurse-administered miniboluses over 120 to 300 seconds. For procedural complications, bradycardia or desaturation (Spo₂ <85%) prompted pausing administration with catheter retention, stimulation, and Fio₂ adjustment until recovery; apnea required immediate positive pressure ventilation; regurgitation was managed by temporary suspension and slowed infusion.

The initial surfactant dose was 100 mg/kg; repeat administration was permitted within 72 hours if it was at least 4 to 6 hours after prior dose, the infant experienced progressive respiratory distress, the infant had chest radiograph-confirmed RDS, and non-RDS etiologies had been excluded. Intubation and IMV within 72 hours or 7 days were indicated for meeting any of the following: (1) severe respiratory acidosis (arterial partial pressure of carbon dioxide [Paco₂] >65 mm Hg with pH <7.2); (2) hypoxemia (Spo₂ <85% on Fio₂ >0.4); (3) recurrent apnea (≥3 episodes/h or any requiring positive pressure ventilation), with an episode of apnea defined centrally as cessation of breathing for more than 20 seconds or a shorter pause accompanied by bradycardia or oxygen desaturation; (4) SAS increase more than 2 points/h or SAS greater than 5 for more than 2 hours after surfactant administration; (5) pulmonary hemorrhage; (6) cardiopulmonary arrest; or (7) clinical judgment of need for escalation, which required confirmation by 2 attending neonatologists and was used only when no objective criteria applied. The extubation criterion was mean airway pressure (MAP) less than 8 cm H₂O with Fio₂ less than 0.3. NIV support weaning required resolved respiratory distress (SAS <3), NCPAP with PEEP 3 to 5 cm H₂O or NIPPV with MAP 6 to 7 cm H₂O at Fio₂ 0.25 or less, or an apnea-free period of at least 24 hours. The different thresholds reflect physiologically comparable support levels and were applied consistently across all centers to ensure uniformity. Caffeine citrate was initiated after admission with a 20-mg/kg loading dose followed by 5 to 10 mg/kg per day maintenance.

Masking

Operators, clinicians, and nurses were not masked to intervention allocation due to procedural requirements, while independent outcome evaluators and data analysts remained masked. Although caregiver masking was not feasible, this design limits performance bias by relying on predefined objective criteria for treatment failure and eliminates detection bias through masked outcome assessment. These criteria included standardized thresholds for respiratory parameters and imaging findings, ensuring consistent adjudication.

Outcomes Assessment

The primary outcome was NIV failure within 72 hours after birth, defined as requiring intubation with IMV. Secondary outcomes included NIV failure within 7 days, surfactant redosing (≥2 doses), and complications, including pneumothorax, pulmonary hemorrhage, pneumonia, persistent pulmonary hypertension of the newborn, hemodynamically significant patent ductus arteriosus,¹³ BPD,¹⁴ severe intraventricular hemorrhage (IVH; grade III-IV per Papile classification),¹⁵ periventricular leukomalacia, blood culture-positive late-onset sepsis, necrotizing enterocolitis (NEC) of any grade,¹⁶ and retinopathy of prematurity. BPD severity was graded using Jensen’s 2019 criteria¹⁴ based on respiratory support at 36 weeks’ PMA: no BPD (no support), grade 1 (nasal cannula ≤2 L/min), grade 2 (>2 L/min or noninvasive ventilation), or grade 3 (IMV). Late-onset sepsis was defined as occurring after 72 hours of age with a positive bacterial or fungal culture from blood. The modified Bell staging system¹⁶ stratifies NEC severity through integrated clinical-radiological criteria: stage I (suspected) demonstrates systemic or abdominal signs without radiographic confirmation; stage II (confirmed), pneumatosis intestinalis or portal venous gas on abdominal imaging; and stage III (advanced), intestinal perforation or hemodynamic instability necessitating surgical intervention. Respiratory support durations (NIV, IMV, and oxygen days), length of hospital stay, and in-hospital mortality were also assessed. Independent outcome assessors, masked to treatment allocation, applied these criteria to all events. Disagreements were resolved by a third blinded adjudicator.

DSMC

The DSMC conducted prescheduled interim analyses at 30% and 60% enrollment to evaluate efficacy and safety end points. These statistical monitoring parameters, including the O’Brien-Fleming α-spending function thresholds (α = .005 at 30% enrollment; α = .038 at 60% enrollment) and stopping rules, were formally documented in the final trial protocol (Supplement 1) approved prior to interim analyses. The DSMC applied 3 prespecified criteria: (1) futility boundary (conditional power <20%), (2) noninferiority margin violation (risk difference >10% with P < .005 at 30% analysis), or (3) protocol-defined safety concerns. This rigorous approach maintained an overall type I error rate of 0.05.

Statistical Analysis

A 2020 trial in preterm infants with 32 weeks’ gestation with RDS reported treatment failure risks of 24.5% with NCPAP and 22.4% with NIPPV using LISA, with no statistically significant difference between the groups.¹⁷ The noninferiority margin was set at 10%, defining NCPAP as noninferior if the upper limit of the 95% CI for the risk difference between groups remained below this threshold. With 80% power (α = .05), 452 infants per group were required. Accounting for 6% potential attrition, the final sample size totaled 960 infants (480 per group) with 1:1 randomization.

The primary intention-to-treat analysis included all randomized eligible infants according to original group assignment. In the primary analysis, primary and secondary outcomes were compared between groups using risk differences for binary outcomes (generalized linear models with binomial distribution or identity link), mean differences for continuous outcomes (linear regression), or median differences for skewed variables (quantile regression), all reported with 95% CIs, calculated using R software version 4.0.2 for i386 architecture (R Project for Statistical Computing). The primary outcome models were adjusted for the stratification factors used in randomization (gestational age, birth weight, infant sex, and maternal corticosteroid use) and included clinical site as a fixed effect to account for center variability. This adjusted analysis was prespecified as a sensitivity analysis for robustness. For secondary outcomes, analyses adjusted for clinical site only to prioritize control of center-level confounding. Missing data for baseline or secondary outcomes were minimal and were handled by using available cases.

The trial was stopped for futility after enrolling 312 infants (32.5% of planned 960) based on a prespecified interim analysis. Using the O’Brien-Fleming α-spending function, the adjusted significance threshold at this stage was α = .014.

To assess the robustness of our findings, a post hoc bayesian analysis was conducted with a neutral prior (normal distribution: mean [SD], 10% [5%]), placing 95% prior probability on the true risk difference being between 0% and 20%. A binomial likelihood model was used for the observed event counts in each group.

P values were 2-sided, and statistical significance was set at α = .05. All analyses were performed using R software version 4.0.2. All analyses followed intention-to-treat principles. Data were analyzed from January 7 to May 9, 2025.

Results

Trial Population

From the 11 participating NICUs, 996 infants were assessed for eligibility. Among them, 670 infants (67.3%) did not meet the inclusion criteria, and an additional 14 infants were not enrolled, resulting in 312 randomized infants who received NCPAP (153 infants) or NIPPV (159 infants) (Figure). Included infants had a median (IQR) gestational age of 28.0 (28.6-29.4) weeks and birth weight of 940.0 (1118.5-1280.0) g; there were 174 boys (55.8%) and 138 girls (44.2%). Baseline demographic and clinical characteristics of the study population were similar between groups (Table 1).

Flowchart of preterm infant screening, exclusions, randomization, and analysis counts. Top center rectangular node with light gray fill and dark border: 996 Preterm infants screened for eligibility. A vertical connector line descends from this node; a right-pointing arrow branches to an upper right light gray box listing exclusions. The exclusions box reads: 670 Excluded infants; 363 Needed intubation; 79 No parental written consent; 77 Enrolled in other study; 64 Missed or identified too late; 55 Other reasons; 20 Suspended congenital anomaly; 12 Not expected to survive. The main vertical line continues downward to a central horizontal oval with light gray fill: 326 Randomized. Two diagonal connector lines extend from the oval to two group allocation boxes. On the left, a light gray rectangle reads 160 N C P A P group. Beneath it, a smaller light gray box connected by a short line contains: 7 Censored infants; 4 Transferred; 2 R D S criteria not met; 1 Intubation prior to M I S A. A vertical connector continues downward to a bottom left light gray rectangle reading 153 Included in primary outcome analysis. On the right, a light gray rectangle reads 166 N I P P V group. Beneath it, a smaller light gray box connected by a short line contains: 7 Censored infants; 3 Transferred; 2 R D S criteria not met; 1 Intubation prior to M I S A; 1 Discharge abandonment. A vertical connector continues downward to a bottom right light gray rectangle reading 159 Included in primary outcome analysis. All connectors are thin gray lines with arrowheads only on the branch from the screening pathway to the exclusions box. — MISA indicates minimal invasive surfactant administration; NCPAP, nasal continuous positive airway pressure; NIPPV, nasal intermittent positive pressure ventilation; and RDS, respiratory distress syndrome.

Table 1. Maternal and Infant Baseline Demographic and Clinical Characteristics.

Characteristic	Individuals, No. (%)
Characteristic	NCPAP (n = 153)	NIPPV (n = 159)
Maternal characteristics
Age at delivery, median (IQR), y	33.0 (30.0 to 36.0)	32.0 (30.0 to 35.0)
Cesarean delivery	87 (56.9)	100 (62.9)
Prolonged rupture of membranes >18 h	33 (21.6)	29 (18.2)
Hypertensive disorders of pregnancy^a	53 (34.6)	47 (29.6)
Gestational diabetes	32 (20.9)	28 (17.6)
In vitro fertilization	47 (30.7)	47 (29.6)
Exposure to any antenatal corticosteroids^b	126 (82.4)	132 (83.0)
Antenatal corticosteroids full course^b	93 (60.8)	98 (61.6)
Infant characteristics
Gestational age at birth, median (IQR), wk	28.5 (27.6 to 29.3)	29.0 (28.1 to 29.4)
Birth weight, median (IQR), g	1120.0 (947.5 to 1270)	1130.0 (950 to 1310)
Birth length, median (IQR), cm	36.0 (34.0 to 38.0)	37.0 (35.0 to 39.0)
Head circumference, median (IQR), cm	26.0 (25.0 to 28.0)	27.0 (25.0 to 28.0)
Sex
Female	64 (41.8)	74 (46.5)
Male	89 (58.2)	85 (53.5)
Small-for-gestational-age,^c	14 (9.2)	12 (7.5)
Multiple birth	54 (35.3)	63 (39.6)
Apgar score, median (IQR)
At 1 min	8.0 (7.0 to 10.0)	8.0 (6.0 to 9.0)
At 5 min	9.0 (8.0 to 10.0)	9.0 (8.0 to 10.0)
At 10 mins	9.0 (9.0 to 10.0)	9.0 (9.0 to 10.0)
Umbilical arterial blood gas analysis
pH,
Median (IQR)	7.3 (7.2 to 7.3)	7.3 (7.2 to 7.3)
No.	66	69
Base excess
Median (IQR), mEq/L	−4.9 (−6.9 to −3.0)	−6.0 (−8.1 to −3.1)
No.	64	67
Lactic acid
Median (IQR), mmol/L	3.0 (1.9 to 4.1)	3.4 (2.3 to 5.0)
No.	64	63
Postnatal age at randomization, median (IQR), min	20.0 (12.0 to 25.5)	20.0 (13.0 to 23.0)
Fio₂ prior to randomization, median (IQR), %	30.0 (30.0 to 40.0)	30.0 (30.0 to 40.0)
SAS prior to randomization
Median (IQR)	5.0 (4.0 to 6.0)	5.0 (4.0 to 6.0)
No.	137	122

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Abbreviations: Fio₂, fraction of inspired oxygen; NCPAP, nasal continuous positive airway pressure; NIPPV, nasal intermittent positive pressure ventilation; SAS, Silverman Anderson score.

SI conversion factor: To convert base excess to millimoles per liter, multiply by 1.

^{^a}

Includes preeclampsia, eclampsia, and hemolysis, elevated liver enzymes, and low platelets syndrome. Preexisting hypertension is not included.

^{^b}

A full course was defined as receiving at least 2 doses.

^{^c}

Defined as birth weight below the 10th percentile of the mean birth weight for the same gestational age or below 2 SDs of the mean birth weight for the same gestational age.

The trial was terminated early in strict adherence to the prespecified stopping rule (risk difference >10% with P < .005 at 30% analysis), as defined in the final trial protocol in Supplement 1, after interim analysis at 30% enrollment demonstrated conclusive inferiority of NCPAP.

Primary Outcome

The primary outcome was available for all infants. The incidence of NIV failure within 72 hours after birth occurred in 40 infants (26.1%) in the NCPAP group compared with 21 infants (13.2%) in the NIPPV group, demonstrating a statistically significant difference (adjusted risk difference, 12.8% [95% CI, 4.2%-21.6%]; P = .004) (Table 2). In sensitivity analysis, the posterior probability that the true risk difference exceeded 10% was 98.7% (95% credible interval, 96.2%-99.8%), suggesting a high likelihood of NCPAP inferiority even if full recruitment had been achieved.

Table 2. Primary and Secondary In-Hospital Outcomes.

Outcomes	Infants, No. (%)		Risk difference, % (95% CI)	P value
Outcomes	NCPAP (n = 153)	NIPPV (n = 159)	Risk difference, % (95% CI)	P value
Primary outcome
NIV failure within 72 h after birth	40 (26.1)	21 (13.2)	12.8 (4.2 to 21.6)^a	.004
Secondary outcomes
NIV failure within 7 d after birth	42 (27.5)	24 (15.1)	12.4 (3.4 to 21.4)	.008
Required >1 doses of surfactant	31 (20.3)	32 (20.1)	0.2 (−8.8 to 9.1)	.98
hsPDA	65 (42.5)	74 (46.5)	−4.1 (−15.1 to 6.9)	.47
PPHN	15 (9.8)	12 (7.6)	2.3 (−4.0 to 8.5)	.48
Pneumonia	24 (15.7)	24 (15.1)	0.6 (−7.4 to 8.6)	.89
Pneumothorax	5 (3.3)	1 (0.6)	2.6 (−0.4 to 5.7)	.09
Pulmonary hemorrhage	11 (7.2)	5 (3.1)	4.1 (−0.9 to 9.0)	.11
BPD grade in survivors at 36 wk, No./total No. (%)^b
None	60/150 (40.0)	63/157 (40.1)	−0.1 (−11.1 to 10.8)	.98
1	66/150 (44.0)	76/157 (48.4)	−4.4 (−15.6 to 6.7)	.44
2	16/150 (10.7)	11/157 (7.0)	3.7 (−2.7 to 10.0)	.26
3	8/150 (5.3)	7/157 (4.5)	0.9 (−4.0 to 5.7)	.72
IVH grade III or IV, No./total No. (%)	3/151 (2.0)	4/158 (2.5)	−0.6 (−3.9 to 2.8)	.75
PVL, No./total (%)	3/151 (2.0)	2/158 (1.3)	0.7 (−2.1 to 3.5)	.62
Late-onset sepsis	28 (18.3)	27 (17.0)	1.3 (−7.1 to 9.8)	.76
NEC	28 (18.3)	17 (10.7)	7.7 (−0.1 to 15.5)	.06
Severe ROP stage ≥2, No./total No. (%)	44/150 (29.3)	44/157 (28.0)	1.3 (−8.8 to 11.4)	.80
In-hospital mortality	3 (2.0)	2 (1.3)	0.7 (−2.1 to 3.5)	.62
Alive at hospital discharge
Total duration of NIV
Median (IQR), d	30.0 (19.0 to 40.0)	31.0 (19.3 to 43.0)	−0.49 (−4.7 to 3.7)	.39
No.	150	157	NA	NA
Total duration of IMV
Median (IQR), h	0.0 (0.0 to 144.0)	0.0 (0.0 to 40.5)	18.5 (−18.5 to 55.5)	.02
No.	150	157	NA	NA
Duration of supplemental oxygen
Median (IQR), d	46.0 (33.8 to 59.0)	45.0 (31.1 to 62.0)	−0.3 (−4.8 to 4.1)	.93
No.	150	157	NA	NA
Length of hospital stay
Median (IQR), d	59.0 (52.0 to 72.0)	57.0 (46.0 to 69.0)	4.1 (−0.4 to 8.6)	.01
No.	150	157	NA	NA
Corrected gestational age at discharge,
Median (IQR), wk	37.1 (36.2 to 38.4)	36.6 (36.0 to 38.1)	0.4 (−0.2 to 0.9)	.13
No.	150	157	NA	NA
Body weight at discharge
Median (IQR), g	2315.0 (2067.5 to 2428.5)	2260.0 (2150.0 to 2490.0)	−0.4 (−1.4 to 0.6)	.72
No.	122	129	NA	NA
Body length at discharge
Median (IQR), cm	45.0 (43.0 to 47.0)	45.0 (44.0 to 46.0)	−0.1 (−0.9 to 0.6)	.83
No.	109	119	NA	NA
Head circumference at discharge
Median (IQR), cm	32.0 (31.0 to 33.0)	32.0 (31.0 to 33.0)	−0.2 (−0.8 to 0.3)	.61
No.	110	119	NA	NA

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Abbreviations: BPD, bronchopulmonary dysplasia; hsPDA, patent ductus arteriosus with hematological symptoms patent; IMV, invasive mechanical ventilation; IVH, intraventricular hemorrhages; NA, not applicable; NCPAP, nasal continuous positive airway pressure; NEC, necrotizing enterocolitis; NIPPV, nasal intermittent positive pressure ventilation; NIV, non-invasive ventilation; PPHN, persistent pulmonary hypertension of newborn; PVL, periventricular leukomalacia; ROP, retinopathy of prematurity.

^{^a}

Adjusted risk difference (NCPAP minus NIPPV) from generalized linear models (binomial, identity link) using marginal probabilities, with covariates: gestational age, birth weight, infant sex, site, and maternal corticosteroid use (clinical site as fixed effect).

Secondary Outcomes

In secondary outcomes, the incidence of NIV failure within 7 days remained significantly higher in the NCPAP group (42 infants [27.5%]) compared with the NIPPV group (24 infants [15.1%]), with risk difference of 12.4% (95% CI, 3.4% to 21.4%) (P = .008). Surfactant redosing rates were similar between groups. No significant differences were observed in complications, including hemodynamically significant patent ductus arteriosus, persistent pulmonary hypertension of the newborn, pneumonia, or severe retinopathy of prematurity. NEC incidence was numerically higher in the NCPAP group, although this difference did not reach statistical significance (28 infants [18.3%] vs 17 infants [10.7%]; risk difference, 7.7% [95% CI, −0.1% to 15.5%]; P = .06). Other outcomes, including pneumothorax, pulmonary hemorrhage, BPD severity grades, intraventricular hemorrhage (grade III or IV), periventricular leukomalacia, late-onset sepsis, and in-hospital mortality, demonstrated no statistically significant intergroup differences. While median durations of NIV, supplemental oxygen, and corrected gestational age at discharge were comparable between groups, the NCPAP group had longer IMV duration (median [IQR], 0.0 [0.0-144.0] hours vs 0.0 [0.0-40.5] hours; P = .02) and extended hospital stays (median [IQR], 59.0 [52.0-72.0] days vs 57.0 [46.0-69.0] days; P = .01). Adverse events during MISA are summarized in eTable 1 in Supplement 2.

Exploratory Outcomes

Exploratory analyses of serial blood gas parameters and vital signs during the first 72 hours after birth revealed no statistically significant differences between the NCPAP and NIPPV groups. Blood gas parameters are provided in eTable 2 in Supplement 2, and vital signs are provide in eTable 3 in Supplement 2.

Discussion

This multicenter, noninferiority randomized clinical trial was terminated early due to conclusive inferiority of NCPAP compared with NIPPV for preterm infants with RSD. It demonstrated that synchronized NIPPV with MISA significantly reduced NIV failure rates compared to NCPAP in extremely preterm infants (24-29⁺⁶ weeks’ gestation). The absolute reduction of 12.8% with NIPPV exceeded the prespecified 10% noninferiority margin, supporting superiority of NIPPV. Baseline characteristics were well-balanced between groups. Despite a minor difference in median gestational age (0.5 weeks), the primary analysis adjusted for this as a stratification factor, and physiological parameters were similar during the first 72 hours, supporting clinical comparability at enrollment.

Secondary outcomes further supported NIPPV’s advantage: NIV failure within 7 days remained significantly lower in the NIPPV group, and infants receiving NIPPV required shorter IMV and hospitalization durations. Surfactant redosing rates were comparable between groups, with no significant differences in most complications. The difference in NEC incidence between groups did not reach statistical significance and warrants cautious interpretation. NEC events were distributed across centers, ruling out site-specific bias. This finding challenges traditional concerns that NIPPV increases NEC risk, as improved respiratory stability with NIPPV might theoretically enhance mesenteric perfusion, although this mechanism remains speculative. Given unstandardized feeding protocols and the study being underpowered for NEC, this finding is hypothesis-generating only and requires confirmation in future trials. The disconnect between early NIV failure reduction and modest long-term benefits underscores the multifactorial nature of neonatal outcomes. Future trials should focus on robust end points (eg, moderate to severe BPD, neurodevelopment) and include mediation analyses to determine whether early respiratory improvement drives long-term benefits.

The superior efficacy of NIPPV likely stems from its multifaceted physiological mechanisms. Intermittent positive pressure enhances alveolar recruitment, mitigates atelectasis, and reduces respiratory muscle fatigue, decreasing the need for early intubation.¹⁸ Synchronized ventilation amplifies these benefits through 3 interdependent pathways^18,19,20: improved pressure transmission to distal airways, increasing transpulmonary pressure and stabilizing chest wall to enhance lung volume and gas exchange; elevated MAP, preventing alveolar collapse and reducing intrapulmonary shunting; and dynamic support, clearing anatomical dead space while providing phasic pressure to stimulate respiratory drive. Together, these mechanisms—alveolar stabilization, optimized pressure dynamics, and respiratory drive modulation—likely explain NIPPV’s capacity to reduce reliance on invasive ventilation compared with NCPAP.

The efficacy of NIPPV vs NCPAP as initial respiratory support for preterm infants, particularly those with less than 30 weeks’ gestation, remains debated. A single-center randomized clinical trial in 216 infants showed NIPPV significantly reduced intubation risk within 72 hours vs CPAP, with trends favoring NIPPV in NIV days, BPD, and hospitalization length.²¹ A meta-analysis of 17 trials and 1958 patients confirmed early NIPPV was associated with reduced respiratory failure and intubation compared with NCPAP in preterm infants (approximately 28-32 weeks’ gestation).²⁰ Conversely, large randomized trials, including one with 1009 infants with birth weight less than 1000 g, found no difference in NIV failure or BPD-free survival between groups.²² A multicenter cohort study of 512 infants similarly reported no IMV reduction within 7 days with NIPPV.²³ These inconsistencies may reflect variations in study populations, protocols, or surfactant timing. A 2016 randomized clinical trial showed NIPPV with MIST reduced IMV within 72 hours in infants with 26 to 32 weeks’ gestation.¹¹ Our findings address the critical evidence gap in infants with less than 30 weeks’ gestation, for whom prior trials were inconsistent.

Current guidelines, including the 2022 European Consensus,² recommend NCPAP as first-line therapy for preterm infants with RDS; however, our findings suggest NIPPV may be more effective for extremely preterm infants. Although NIPPV’s respiratory benefits must be weighed against potential risks, such as abdominal distension and NEC, we found numerically higher NEC incidence with NCPAP, although the difference was not statistically significant. Current evidence on whether synchronized NIPPV influences NEC risk remains inconclusive, with some studies suggesting minimal to no effect but overall certainty being low.^11,24 Therefore, vigilant monitoring remains essential.

Limitations

This trial has several methodological limitations. First, despite rigorous prespecified stopping rules (O’Brien-Fleming adjusted α = .005) and DSMC oversight, the reduced sample size may overestimate treatment effect and limit the precision. Second, absence of long-term neurodevelopmental and pulmonary follow-up precludes assessment of sustained outcomes (eg, BPD severity, cognitive impairment), essential for comprehensive evaluation. Future multicenter trials with extended follow-up should validate these outcomes. Additionally, further investigation is needed to optimize NIPPV parameters (eg, synchronization algorithms, pressure settings). Therefore, generalizability to settings using nonsynchronized NIPPV or different MISA techniques should be approached with caution.

Conclusions

In this randomized clinical trial of extremely preterm infants (24-29⁺⁶ weeks’ gestation) with RDS, synchronized NIPPV with MISA significantly reduced NIV failure within 72 hours and was associated with shorter IMV duration compared with NCPAP. These findings support re-evaluating current guidelines to consider NIPPV as a primary strategy, particularly in high-risk populations. However, given early termination and limited events, these results should be interpreted cautiously; further research is needed to confirm long-term benefits and broader generalizability.

Supplement 1.

Trial Protocol and Statistical Analysis Plan

jamanetwopen-e2619785-s001.pdf^{(766.3KB, pdf)}

Supplement 2.

eTable 1. Procedure-Related Adverse Events During MISA

eTable 2. Blood Gas Comparison Between 2 Groups at 4 Time Points

eTable 3. Comparison of Vital Signs Within 72 h After Birth Between 2 Groups

jamanetwopen-e2619785-s002.pdf^{(325KB, pdf)}

Supplement 3.

Data Sharing Statement

jamanetwopen-e2619785-s003.pdf^{(16.7KB, pdf)}

References

1.Stoll BJ, Hansen NI, Bell EF, et al. ; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network . Trends in care practices, morbidity, and mortality of extremely preterm neonates, 1993-2012. JAMA. 2015;314(10):1039-1051. doi: 10.1001/jama.2015.10244 [DOI] [PMC free article] [PubMed] [Google Scholar]
2.Sweet DG, Carnielli VP, Greisen G, et al. European consensus guidelines on the management of respiratory distress syndrome: 2022 update. Neonatology. 2023;120(1):3-23. doi: 10.1159/000528914 [DOI] [PMC free article] [PubMed] [Google Scholar]
3.Abiramalatha T, Ramaswamy VV, Bandyopadhyay T, et al. Interventions to prevent bronchopulmonary dysplasia in preterm neonates: an umbrella review of systematic reviews and meta-analyses. JAMA Pediatr. 2022;176(5):502-516. doi: 10.1001/jamapediatrics.2021.6619 [DOI] [PubMed] [Google Scholar]
4.Abdel-Latif ME, Davis PG, Wheeler KI, De Paoli AG, Dargaville PA. Surfactant therapy via thin catheter in preterm infants with or at risk of respiratory distress syndrome. Cochrane Database Syst Rev. 2021;5(5):CD011672. [DOI] [PMC free article] [PubMed] [Google Scholar]
5.Han T, Liu H, Zhang H, et al. Minimally invasive surfactant administration for the treatment of neonatal respiratory distress syndrome: a multicenter randomized study in China. Front Pediatr. 2020;8:182. doi: 10.3389/fped.2020.00182 [DOI] [PMC free article] [PubMed] [Google Scholar]
6.Isayama T, Iwami H, McDonald S, Beyene J. Association of noninvasive ventilation strategies with mortality and bronchopulmonary dysplasia among preterm infants: a systematic review and meta-analysis. JAMA. 2016;316(6):611-624. doi: 10.1001/jama.2016.10708 [DOI] [PubMed] [Google Scholar]
7.Zhu X, Li F, Shi Y, Feng Z, De Luca D; Nasal Oscillation Post-Extubation (NASONE) Study Group . Effectiveness of nasal continuous positive airway pressure vs nasal intermittent positive pressure ventilation vs noninvasive high-frequency oscillatory ventilation as support after extubation of neonates born extremely preterm or with more severe respiratory failure: a secondary analysis of a randomized clinical trial. JAMA Netw Open. 2023;6(7):e2321644. doi: 10.1001/jamanetworkopen.2023.21644 [DOI] [PMC free article] [PubMed] [Google Scholar]
8.Zhu X, Qi H, Feng Z, Shi Y, De Luca D; Nasal Oscillation Post-Extubation (NASONE) Study Group . Noninvasive high-frequency oscillatory ventilation vs nasal continuous positive airway pressure vs nasal intermittent positive pressure ventilation as postextubation support for preterm neonates in china: a randomized clinical trial. JAMA Pediatr. 2022;176(6):551-559. doi: 10.1001/jamapediatrics.2022.0710 [DOI] [PMC free article] [PubMed] [Google Scholar]
9.Garland JS, Nelson DB, Rice T, Neu J. Increased risk of gastrointestinal perforations in neonates mechanically ventilated with either face mask or nasal prongs. Pediatrics. 1985;76(3):406-410. doi: 10.1542/peds.76.3.406 [DOI] [PubMed] [Google Scholar]
10.Lemyre B, Davis PG, De Paoli AG, Kirpalani H. Nasal intermittent positive pressure ventilation (NIPPV) versus nasal continuous positive airway pressure (NCPAP) for preterm neonates after extubation. Cochrane Database Syst Rev. 2017;2(2):CD003212. doi: 10.1002/14651858.CD003212.pub3 [DOI] [PMC free article] [PubMed] [Google Scholar]
11.Oncel MY, Arayici S, Uras N, et al. Nasal continuous positive airway pressure versus nasal intermittent positive-pressure ventilation within the minimally invasive surfactant therapy approach in preterm infants: a randomised controlled trial. Arch Dis Child Fetal Neonatal Ed. 2016;101(4):F323-F328. doi: 10.1136/archdischild-2015-308204 [DOI] [PubMed] [Google Scholar]
12.Zhang H, Li J, Zeng L, et al. A multicenter, randomized controlled, non-inferiority trial, comparing nasal continuous positive airway pressure with nasal intermittent positive pressure ventilation as primary support before minimally invasive surfactant administration for preterm infants with respiratory distress syndrome (the NIV-MISA-RDS trial): Study protocol. Front Pediatr. 2022;10(10):968462. doi: 10.3389/fped.2022.968462 [DOI] [PMC free article] [PubMed] [Google Scholar]
13.Hamrick SEG, Sallmon H, Rose AT, et al. Patent ductus arteriosus of the preterm infant. Pediatrics. 2020;146(5):e20201209. doi: 10.1542/peds.2020-1209 [DOI] [PMC free article] [PubMed] [Google Scholar]
14.Jensen EA, Dysart K, Gantz MG, et al. The diagnosis of bronchopulmonary dysplasia in very preterm infants. an evidence-based approach. Am J Respir Crit Care Med. 2019;200(6):751-759. doi: 10.1164/rccm.201812-2348OC [DOI] [PMC free article] [PubMed] [Google Scholar]
15.Papile LA, Burstein J, Burstein R, Koffler H. Incidence and evolution of subependymal and intraventricular hemorrhage: a study of infants with birth weights less than 1,500 gm. J Pediatr. 1978;92(4):529-534. doi: 10.1016/S0022-3476(78)80282-0 [DOI] [PubMed] [Google Scholar]
16.Bell MJ, Ternberg JL, Feigin RD, et al. Neonatal necrotizing enterocolitis: therapeutic decisions based upon clinical staging. Ann Surg. 1978;187(1):1-7. doi: 10.1097/00000658-197801000-00001 [DOI] [PMC free article] [PubMed] [Google Scholar]
17.Szczapa T, Hożejowski R, Krajewski P, Group S; Study Group . Implementation of less invasive surfactant administration in clinical practice—experience of a mid-sized country. PLoS One. 2020;15(7):e0235363. doi: 10.1371/journal.pone.0235363 [DOI] [PMC free article] [PubMed] [Google Scholar]
18.Moretti C, Gizzi C. Synchronized nasal intermittent positive pressure ventilation. Clin Perinatol. 2021;48(4):745-759. doi: 10.1016/j.clp.2021.07.005 [DOI] [PubMed] [Google Scholar]
19.Ramaswamy VV, More K, Roehr CC, Bandiya P, Nangia S. Efficacy of noninvasive respiratory support modes for primary respiratory support in preterm neonates with respiratory distress syndrome: systematic review and network meta-analysis. Pediatr Pulmonol. 2020;55(11):2940-2963. doi: 10.1002/ppul.25011 [DOI] [PubMed] [Google Scholar]
20.Lemyre B, Deguise MO, Benson P, Kirpalani H, Ekhaguere OA, Davis PG. Early nasal intermittent positive pressure ventilation (NIPPV) versus early nasal continuous positive airway pressure (NCPAP) for preterm infants. Cochrane Database Syst Rev. 2023;7(7):CD005384. [DOI] [PMC free article] [PubMed] [Google Scholar]
21.Dey R, Sardar SK, Kumar Saha A, Mukherjee S. Nonsynchronized nasal intermittent positive pressure ventilation versus continuous positive airway pressure as a primary mode of respiratory support in neonates (26-40 weeks) admitted in a tertiary care center: a randomized controlled trial. Pediatr Pulmonol. 2023;58(11):3063-3070. doi: 10.1002/ppul.26624 [DOI] [PubMed] [Google Scholar]
22.Kirpalani H, Millar D, Lemyre B, Yoder BA, Chiu A, Roberts RS; NIPPV Study Group . A trial comparing noninvasive ventilation strategies in preterm infants. N Engl J Med. 2013;369(7):611-620. doi: 10.1056/NEJMoa1214533 [DOI] [PubMed] [Google Scholar]
23.Cao H, Li H, Zhu X, et al. Three non-invasive ventilation strategies for preterm infants with respiratory distress syndrome: a propensity score analysis. Arch Med Sci. 2020;16(6):1319-1326. doi: 10.5114/aoms.2020.93541 [DOI] [PMC free article] [PubMed] [Google Scholar]
24.Dursun M, Uslu S, Bulbul A, Celik M, Zubarioglu U, Bas EK. Comparison of early nasal intermittent positive pressure ventilation and nasal continuous positive airway pressure in preterm infants with respiratory distress syndrome. J Trop Pediatr. 2019;65(4):352-360. doi: 10.1093/tropej/fmy058 [DOI] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplement 1.

Trial Protocol and Statistical Analysis Plan

jamanetwopen-e2619785-s001.pdf^{(766.3KB, pdf)}

Supplement 2.

eTable 1. Procedure-Related Adverse Events During MISA

eTable 2. Blood Gas Comparison Between 2 Groups at 4 Time Points

eTable 3. Comparison of Vital Signs Within 72 h After Birth Between 2 Groups

jamanetwopen-e2619785-s002.pdf^{(325KB, pdf)}

Supplement 3.

Data Sharing Statement

jamanetwopen-e2619785-s003.pdf^{(16.7KB, pdf)}

[zoi260546r1] 1.Stoll BJ, Hansen NI, Bell EF, et al. ; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network . Trends in care practices, morbidity, and mortality of extremely preterm neonates, 1993-2012. JAMA. 2015;314(10):1039-1051. doi: 10.1001/jama.2015.10244 [DOI] [PMC free article] [PubMed] [Google Scholar]

[zoi260546r2] 2.Sweet DG, Carnielli VP, Greisen G, et al. European consensus guidelines on the management of respiratory distress syndrome: 2022 update. Neonatology. 2023;120(1):3-23. doi: 10.1159/000528914 [DOI] [PMC free article] [PubMed] [Google Scholar]

[zoi260546r3] 3.Abiramalatha T, Ramaswamy VV, Bandyopadhyay T, et al. Interventions to prevent bronchopulmonary dysplasia in preterm neonates: an umbrella review of systematic reviews and meta-analyses. JAMA Pediatr. 2022;176(5):502-516. doi: 10.1001/jamapediatrics.2021.6619 [DOI] [PubMed] [Google Scholar]

[zoi260546r4] 4.Abdel-Latif ME, Davis PG, Wheeler KI, De Paoli AG, Dargaville PA. Surfactant therapy via thin catheter in preterm infants with or at risk of respiratory distress syndrome. Cochrane Database Syst Rev. 2021;5(5):CD011672. [DOI] [PMC free article] [PubMed] [Google Scholar]

[zoi260546r5] 5.Han T, Liu H, Zhang H, et al. Minimally invasive surfactant administration for the treatment of neonatal respiratory distress syndrome: a multicenter randomized study in China. Front Pediatr. 2020;8:182. doi: 10.3389/fped.2020.00182 [DOI] [PMC free article] [PubMed] [Google Scholar]

[zoi260546r6] 6.Isayama T, Iwami H, McDonald S, Beyene J. Association of noninvasive ventilation strategies with mortality and bronchopulmonary dysplasia among preterm infants: a systematic review and meta-analysis. JAMA. 2016;316(6):611-624. doi: 10.1001/jama.2016.10708 [DOI] [PubMed] [Google Scholar]

[zoi260546r7] 7.Zhu X, Li F, Shi Y, Feng Z, De Luca D; Nasal Oscillation Post-Extubation (NASONE) Study Group . Effectiveness of nasal continuous positive airway pressure vs nasal intermittent positive pressure ventilation vs noninvasive high-frequency oscillatory ventilation as support after extubation of neonates born extremely preterm or with more severe respiratory failure: a secondary analysis of a randomized clinical trial. JAMA Netw Open. 2023;6(7):e2321644. doi: 10.1001/jamanetworkopen.2023.21644 [DOI] [PMC free article] [PubMed] [Google Scholar]

[zoi260546r8] 8.Zhu X, Qi H, Feng Z, Shi Y, De Luca D; Nasal Oscillation Post-Extubation (NASONE) Study Group . Noninvasive high-frequency oscillatory ventilation vs nasal continuous positive airway pressure vs nasal intermittent positive pressure ventilation as postextubation support for preterm neonates in china: a randomized clinical trial. JAMA Pediatr. 2022;176(6):551-559. doi: 10.1001/jamapediatrics.2022.0710 [DOI] [PMC free article] [PubMed] [Google Scholar]

[zoi260546r9] 9.Garland JS, Nelson DB, Rice T, Neu J. Increased risk of gastrointestinal perforations in neonates mechanically ventilated with either face mask or nasal prongs. Pediatrics. 1985;76(3):406-410. doi: 10.1542/peds.76.3.406 [DOI] [PubMed] [Google Scholar]

[zoi260546r10] 10.Lemyre B, Davis PG, De Paoli AG, Kirpalani H. Nasal intermittent positive pressure ventilation (NIPPV) versus nasal continuous positive airway pressure (NCPAP) for preterm neonates after extubation. Cochrane Database Syst Rev. 2017;2(2):CD003212. doi: 10.1002/14651858.CD003212.pub3 [DOI] [PMC free article] [PubMed] [Google Scholar]

[zoi260546r11] 11.Oncel MY, Arayici S, Uras N, et al. Nasal continuous positive airway pressure versus nasal intermittent positive-pressure ventilation within the minimally invasive surfactant therapy approach in preterm infants: a randomised controlled trial. Arch Dis Child Fetal Neonatal Ed. 2016;101(4):F323-F328. doi: 10.1136/archdischild-2015-308204 [DOI] [PubMed] [Google Scholar]

[zoi260546r12] 12.Zhang H, Li J, Zeng L, et al. A multicenter, randomized controlled, non-inferiority trial, comparing nasal continuous positive airway pressure with nasal intermittent positive pressure ventilation as primary support before minimally invasive surfactant administration for preterm infants with respiratory distress syndrome (the NIV-MISA-RDS trial): Study protocol. Front Pediatr. 2022;10(10):968462. doi: 10.3389/fped.2022.968462 [DOI] [PMC free article] [PubMed] [Google Scholar]

[zoi260546r13] 13.Hamrick SEG, Sallmon H, Rose AT, et al. Patent ductus arteriosus of the preterm infant. Pediatrics. 2020;146(5):e20201209. doi: 10.1542/peds.2020-1209 [DOI] [PMC free article] [PubMed] [Google Scholar]

[zoi260546r14] 14.Jensen EA, Dysart K, Gantz MG, et al. The diagnosis of bronchopulmonary dysplasia in very preterm infants. an evidence-based approach. Am J Respir Crit Care Med. 2019;200(6):751-759. doi: 10.1164/rccm.201812-2348OC [DOI] [PMC free article] [PubMed] [Google Scholar]

[zoi260546r15] 15.Papile LA, Burstein J, Burstein R, Koffler H. Incidence and evolution of subependymal and intraventricular hemorrhage: a study of infants with birth weights less than 1,500 gm. J Pediatr. 1978;92(4):529-534. doi: 10.1016/S0022-3476(78)80282-0 [DOI] [PubMed] [Google Scholar]

[zoi260546r16] 16.Bell MJ, Ternberg JL, Feigin RD, et al. Neonatal necrotizing enterocolitis: therapeutic decisions based upon clinical staging. Ann Surg. 1978;187(1):1-7. doi: 10.1097/00000658-197801000-00001 [DOI] [PMC free article] [PubMed] [Google Scholar]

[zoi260546r17] 17.Szczapa T, Hożejowski R, Krajewski P, Group S; Study Group . Implementation of less invasive surfactant administration in clinical practice—experience of a mid-sized country. PLoS One. 2020;15(7):e0235363. doi: 10.1371/journal.pone.0235363 [DOI] [PMC free article] [PubMed] [Google Scholar]

[zoi260546r18] 18.Moretti C, Gizzi C. Synchronized nasal intermittent positive pressure ventilation. Clin Perinatol. 2021;48(4):745-759. doi: 10.1016/j.clp.2021.07.005 [DOI] [PubMed] [Google Scholar]

[zoi260546r19] 19.Ramaswamy VV, More K, Roehr CC, Bandiya P, Nangia S. Efficacy of noninvasive respiratory support modes for primary respiratory support in preterm neonates with respiratory distress syndrome: systematic review and network meta-analysis. Pediatr Pulmonol. 2020;55(11):2940-2963. doi: 10.1002/ppul.25011 [DOI] [PubMed] [Google Scholar]

[zoi260546r20] 20.Lemyre B, Deguise MO, Benson P, Kirpalani H, Ekhaguere OA, Davis PG. Early nasal intermittent positive pressure ventilation (NIPPV) versus early nasal continuous positive airway pressure (NCPAP) for preterm infants. Cochrane Database Syst Rev. 2023;7(7):CD005384. [DOI] [PMC free article] [PubMed] [Google Scholar]

[zoi260546r21] 21.Dey R, Sardar SK, Kumar Saha A, Mukherjee S. Nonsynchronized nasal intermittent positive pressure ventilation versus continuous positive airway pressure as a primary mode of respiratory support in neonates (26-40 weeks) admitted in a tertiary care center: a randomized controlled trial. Pediatr Pulmonol. 2023;58(11):3063-3070. doi: 10.1002/ppul.26624 [DOI] [PubMed] [Google Scholar]

[zoi260546r22] 22.Kirpalani H, Millar D, Lemyre B, Yoder BA, Chiu A, Roberts RS; NIPPV Study Group . A trial comparing noninvasive ventilation strategies in preterm infants. N Engl J Med. 2013;369(7):611-620. doi: 10.1056/NEJMoa1214533 [DOI] [PubMed] [Google Scholar]

[zoi260546r23] 23.Cao H, Li H, Zhu X, et al. Three non-invasive ventilation strategies for preterm infants with respiratory distress syndrome: a propensity score analysis. Arch Med Sci. 2020;16(6):1319-1326. doi: 10.5114/aoms.2020.93541 [DOI] [PMC free article] [PubMed] [Google Scholar]

[zoi260546r24] 24.Dursun M, Uslu S, Bulbul A, Celik M, Zubarioglu U, Bas EK. Comparison of early nasal intermittent positive pressure ventilation and nasal continuous positive airway pressure in preterm infants with respiratory distress syndrome. J Trop Pediatr. 2019;65(4):352-360. doi: 10.1093/tropej/fmy058 [DOI] [PubMed] [Google Scholar]

PERMALINK

Nasal Continuous Positive Airway Pressure vs Nasal Intermittent Positive Pressure Ventilation in Preterm Infants With Respiratory Distress Syndrome

Hui Zhang, MD

Yijia Zhang, MD

Lin Zeng, PhD

Xiaomei Tong, MMed

Meihua Piao, MMed

Haiying He, MMed

Changliang Zhao, BM

Hua Xie, BM

Zhi Zheng, BM

Qiliang Cui, MD

Yiyu Lai, MMed

Huiping Wang, MD

Li Wang, MD

Hongyan Liu, MMed

Xiuying Tian, BM

Hui Wu, MD

Lan Kang, MD

Tongyan Han, MD

Key Points

Question

Findings

Meaning

Abstract

Importance

Objective

Design, Setting, and Participants

Intervention

Main Outcomes and Measures

Results

Conclusions and Relevance

Trial Registration

Introduction

Methods

Study Design

Inclusion and Exclusion Criteria

Randomization

Protocol

Masking

Outcomes Assessment

DSMC

Statistical Analysis

Results

Trial Population

Figure. Patient Recruitment and Randomization Flowchart.

Table 1. Maternal and Infant Baseline Demographic and Clinical Characteristics.

Primary Outcome

Table 2. Primary and Secondary In-Hospital Outcomes.

Secondary Outcomes

Exploratory Outcomes

Discussion

Limitations

Conclusions

References

Associated Data

Supplementary Materials

ACTIONS

PERMALINK

RESOURCES

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