NHFOV vs. NCPAP as a Primary Treatment to Neonatal Respiratory Distress Syndrome(NRDS)

Noninvasive Ventilation for Preterm Neonates With Respiratory Distress Syndrome: a Multi-center Randomized Controlled Trial

Guiyang Maternity and Child Health Care Hospital, Daping Hospital and the Research Institute of Surgery of the Third Military Medical University, Children's Hospital of Chongqing Medical University, Chongqing Maternal and Child Health Hospital, The Second Hospital of Shandong University, Yan'an Affiliated Hospital of Kunming Medical University, The Children's Hospital of Zhejiang University School of Medicine, Hunan Children's Hospital, Zhengzhou Children's Hospital, China, Chengdu Women's and Children's Central Hospital, The People's Hospital of Dehong Autonomous Prefecture, Kunming Children's Hospital, Chongqing Three Gorges Central Hospital, Shanxi Provincial Maternity and Children's Hospital, University of Southern California, Vilnius University, Children's Hospital of Fudan University, Guangdong Women and Children Hospital, Nanjing Children's Hospital

The investigators compared advantages and disadvantages of two forms of noninvasive respiratory support -noninvasive high-frequency oscillatory ventilation (nHFOV) or nasal continuous positive airway pressure (nCPAP) -as a primary mode of ventilation in premature infants with RDS．

Background: Invasive mechanical ventilation is associated with development of adverse pulmonary and non-pulmonary outcomes in very low birth weight infants. Various modes of non-invasive respiratory support are being increasingly used to minimize the incidence of bronchopulmonary dysplasia (BPD). The aim of this trials to compare the effect of noninvasive high-frequency oscillatory ventilation (NHFOV) and nasal continuous positive airway pressure (NCPAP) in preterm infants with respiratory distress syndrome (RDS) as a primary noninvasive ventilation support mode. Methods/Design:In this multicenter, randomized, controlled trial, 300 preterm infants at gestational age (GA) less than 34 weeks with a diagnosis of RDS will be randomized to NHFOV or NCPAP as a primary mode of non-invasive respiratory support. Study will be conducted in 18 tertiary neonatal intensive care units in China. The primary outcome is the need for invasive mechanical ventilation (IMV)during the first 7 days after enrollment in preterm infants randomized to the two groups. The secondary outcomes include days of hospitalization, days on noninvasive respiratory support, days on IMV, days on supplemental oxygen, mortality, need for surfactant, incidence of retinopathy of prematurity(ROP) and bronchopulmonary dysplasia(BPD), occurrence of abdominal distention, air leaks, intraventricular hemorrhage (IVH ≥ grade 3) and necrotizing enterocolitis (NEC> II stage). Other secondary outcomes include scores of Bayley Scales of Infant Development at 2 months and 2 years of corrected age.

nasal continuous positive airway pressure (nCPAP) - as a primary mode of ventilation in premature infants with RDS

noninvasive high-frequency ventilation (nHFOV) as a primary mode of ventilation in premature infants with RDS

NHFOV will be provided by a high frequency ventilator (CNO, Medin, Germany or SLE 5000, UK). NHFOV will be provided via binasal prongs.

Infants assigned to the NCPAP group will be started on a pressure of 6 cmH2O (range: 6-8 cmH2O) by CPAP system (CNO Medin, Germany, Carefusion, USA)

The criteria for endotracheal mechanical ventilation were as follows: severe respiratory acidosis (PaCO2 > 60 mmHg with pH<7.20), severe apnea and bradycardia (defined as recurrent apnea with > 3 episodes per hour associated with heart rate < 100/min, a single episode of apnea that required bag and mask ventilation), hypoxia (FiO2>0.5 with PaO2<50mmHg), severe respiratory distress, neonatal pulmonary hemorrhage, and cardiopulmonary arrest without effective resuscitation needing continued ventilation and rescue

The criteria for intraventricular hemorrhage (IVH, ≥ grade Ⅲ): intraventricular hemorrhage with ventricular dilatation and intraventricular hemorrhage with paren- ehymal hemorrhage. Intraventricular hemorrhage (≥ grade Ⅲ) is worse outcome.

The criteria for neonatal necrotizing enterocolitis(>stage II): Unequivocal malfunction of the gastrointestinal tract is demonstrated clinically and by radiographic evaluation. Other disorders such as malrotation and volvulus and Hirschsprung's disease must be excluded. Neonatal necrotizing enterocolitis(>stage II) is worse outcome

The criteria for Retinopathy of prematurity (>Stage II); extraretinal fibrovascular proliferation neovascularization extends from ridge into the vitreous. Retinopathy of prematurity (>Stage II) is worse outcome.

BPD was defined according to the National Institutes of Health consensus definition: Need for O2 supplementation(FiO2>0.21) for at least 28 days after birth. BPD is worse outcome.

Inclusion criteria: (1)Gestational age (GA) is from 26 to 34 weeks; (2) diagnosis of RDS. The diagnosis of RDS will be based on clinical manifestations (tachypnea, nasal flaring and or grunting) and chest X-ray findings; (3) RDS Silverman score>5; (4) informed parental consent has been obtained. Exclusion criteria (1) severe RDS requiring early intubation according to the American Academy of Pediatrics guidelines for neonatal resuscitation7; (2)major congenital malformations or complex congenital heart disease; (3) group B hemolytic streptococcus pneumonia, septicemia, pneumothorax, pulmonary hemorrhage; (4) cardiopulmonary arrest needing prolonged resuscitation; (5) transferred out of the NICUs without treatment.

Dr. Kris Sekar, Professor of Pediatrics, Oklahoma University Medical Center, Oklahoma, Dr. Jatinder Bhatia, Professor of Pediatrics, Medical College of Georgia, Georgia Health Sciences University, Augusta, Georgia, and Dr. Rowena Cayabyab, MD., MPH (Biostatistics and Epidemiology) Assistant Professor of Pediatrics, Keck School of Medicine of the University of Southern California, Los Angeles, California will serve as DSMB members. Dr. Cayabyab will also serve as consultant for statistical analysis.

Zhu X, Feng Z, Liu C, Shi L, Shi Y, Ramanathan R; NHFOV study group. Nasal High-Frequency Oscillatory Ventilation in Preterm Infants with Moderate Respiratory Distress Syndrome: A Multicenter Randomized Clinical Trial. Neonatology. 2021;118(3):325-331. doi: 10.1159/000515226. Epub 2021 Apr 7.

Zhu XW, Shi Y, Shi LP, Liu L, Xue J, Ramanathan R; NHFOV Study Group. Non-invasive high-frequency oscillatory ventilation versus nasal continuous positive airway pressure in preterm infants with respiratory distress syndrome: Study protocol for a multi-center prospective randomized controlled trial. Trials. 2018 Jun 14;19(1):319. doi: 10.1186/s13063-018-2673-9.