A single-center study comparing high-frequency oscillatory ventilation (HFOV) with conventional mechanical ventilation (CMV) in preterm infants with neonatal ARDS (NARDS) suggests HFOV may reduce the incidence of bronchopulmonary dysplasia (BPD) more effectively.1
In the original report, the HFOV benefit cited ranged from 8% to 32%, depending on the BPD definition used. However, a reanalysis of the original data revealed a numerical error, leading to a correction that now puts the benefit range at 24% to 32%, depending on the BPD definition.
“The corrected BPD result suggests a clinically relevant advantage of HFOV for well-defined NARDS cases,” said senior author Ling-Jun Li, MD, PhD, Associate Professor of Obstetrics & Gynecology, Li Ka-Shing Faculty of Medicine at the University of Hong Kong. “These data support considering HFOV as a potential strategy in carefully phenotyped preterm infants with NARDS. Clinicians should balance potential benefits against center experience, equipment, and monitoring capabilities.”
Animal studies have suggested that HFOV may improve oxygenation and gas exchange, thereby reducing BPD, but human trials have been inconsistent. Principal investigator Long Chen, MD, PhD, Professor and Senior Consultant in Neonatology, Chongqing Health Center for Women and Children, Chongqing Medical University, Chongqing, China, said that animal models typically induce pure respiratory distress syndrome (RDS), which is treated with surfactant alone. In clinical practice, respiratory distress has multiple causes—including placental insufficiency and intrauterine infection—that require multiple interventions.
RDS is largely a restrictive syndrome with little to no lung inflammation that usually responds well to surfactant plus supportive therapy, he explained. NARDS combines restrictive and obstructive physiology with elevated inflammatory markers in the lung.
“Many [clinical] trials mixed heterogeneous groups broadly labeled as ‘respiratory distress’ without distinguishing RDS from NARDS,” Dr. Chen said. “The evidence gap is a lack of hypothesis-driven randomized controlled trials focused on a well-defined clinical population: preterm infants with NARDS. This trial was designed to fill that gap by testing HFOV in clinically adjudicated NARDS, avoiding misclassification, and clarifying context-specific efficacy.”
CMV delivers larger, low-frequency breaths, which enable synchronized patient-ventilator interaction with precise control of tidal volume and positive end-expiratory pressure. HFOV uses very small tidal volumes at high frequency on a constant mean airway pressure. The approach reduces airway resistance and the work of breathing, and improves alveolar recruitment, oxygenation, and compliance, thereby limiting cyclic overdistension and repeated opening-closing injury and attenuating inflammatory responses. The approach may help mitigate ventilatory-induced injuries in preterm infants.
The trial randomized 386 preterm infants to elective HFOV (181 infants) or CMV (205 infants). The mean gestational age was about 30.5 weeks, and 59.6% of the participants were male. The primary outcome was the incidence of BPD by two definitions—as outlined in the 2001 paper from the National Institute of Child Health and Human Development (NICHD) in Pediatrics and the 2019 paper from Erik A. Jensen, MD, MSCE, in the American Journal of Respiratory and Critical Care Medicine.2–3 Secondary outcomes included death, total ventilation duration, air leak, and other major adverse neonatal outcomes.
A total of 39.9% infants developed BPD using the 2001 NICHD guidelines, 34.3% on HFOV vs 44.9% on CMV, for a corrected risk ratio (RR) of 0.76 (95% CI, 0.59-0.98). The absolute difference was smaller using the 2019 Jensen definition, 17.1% vs 25.4%, RR 0.68 (95% CI, 0.45-1.00). There were no significant differences between the groups for any secondary outcomes.
“The reduced BPD incidence with HFOV aligns with our hypothesis,” Dr. Chen said. “HFOV has a clear theoretical advantage over CMV in minimizing volutrauma, atelectrauma, and inflammation. Many prior trials reported little or no benefit largely because they mixed NARDS with RDS. RDS responds to surfactant therapy, whereas NARDS lacks a specific drug treatment and requires supportive ventilation. By excluding RDS and testing HFOV in a pure NARDS population, our study assessed the group most likely to benefit, allowing the effect to emerge.”
The authors noted that the results need to be verified in larger, multicenter populations that more closely reflect the global NARDS burden. Dr. Li said neonatologists worldwide need to collaborate to implement rapid RDS exclusion protocols at admission, standardize NARDS diagnostic pathways, and adopt common criteria in future trials and local audits.
“Clinicians should only consider applying these results where RDS has been confidently excluded and the diagnosis of NARDS is clear,” she said. “For neonatologists, a crucial prerequisite for applying our findings is early exclusion of RDS so true NARDS can be identified—this is essential. Reduced BPD can lower long-term respiratory morbidity and health care use.”
References
1. Li J, Liu K, Yang Q, et al. High-frequency oscillation vs mechanical ventilation for neonatal acute respiratory distress syndrome: a randomized clinical trial. JAMA Netw Open. 2026;9(3):e260268. doi:10.1001/jamanetworkopen.2026.0268
2. Ehrenkranz RA, Walsh MC, Vohr BR, et al. Validation of the National Institutes of Health consensus definition of bronchopulmonary dysplasia. Pediatrics. 2005;116(6):1353-1360. doi:10.1542/peds.2005-0249
3. 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
