Introduction High-flow ventilation support (HF) recruits during exhalation, avoids volutrauma, improves gas exchange and reduced mortality of adults with acute respiratory failure. HF lowers functional dead space by molecular mixing of respiratory gases, analogous to high-frequency oscillatory ventilation (HFOV). A combination of HF and negative-pressure ventilation has managed respiratory failure encountered in a patient with muscular dystrophy. This study aimed to assess the clinical benefit (CB) of avoiding static or cyclic positive pressure ventilation (PPV) in neonates with non-invasive(NI) or invasive(I) HFOV.

Methods Prospero registered (CRD42022327304) systematic review of the CB effect size of HFOV in neonates with respiratory distress syndrome.

Results CB assessed by random effects of composite adverse events (AE) including BPD, IVH, NEC or death in neonates treated with HFOV (n=3116) or PPV (n=3623) from 40 studies; OR=0.628 (95%CI 0.52-0.77), p<0.001, PI 0.27-1.49); or need for intubation (n=8) Knapp-Hartung Adjustment OR=0.495 (95%CI 0.36-0.68), p=0.0006, PI 0.32-0.77). Mixed effects comparison of NI (n=10) and I HFOV (n=30) on AE: NI OR 0.69 (95%CI 0.53-0.9) p=0.007, I OR 0.603 (95%CI 0.47-078) p<0.001, Q=0.5, p=0.48 and HFOV comparison with APRV, CMV and CPAP, Q=1, p=0.6.

Conclusion Neonates treated with HFOV developed less AE and had fewer intubations. NI and I modes of HFOV were beneficial.  Ventilation that avoids static or cyclic supraphysiologic inspiratory positive pressure may redefine lung-protective ventilation strategies. Is it time to consider a mixed high-flow/oscillatory-negative pressure ventilation strategy for patients with vulnerable lungs to prevent VILI?