Nasal High Frequency Oscillation Ventilation Versus Nasal Continuous Positive Airway Pressure to Reduce Post-extubation pCO2 in Very Low Birth Weight Infants: a Randomized Controlled Trial
Phase: NA
Conditions: Respiratory Distress Syndrome, Newborn, Respiratory Tract Diseases
Sponsor: Charite University, Berlin, Germany

Nasal high frequency oscillation ventilation versus nCPAP to 
reduce post-extubation pCO2 in very low birth weight infants: a 
randomized controlled trial 
 
Objectives 
To investigate whether nasal high frequency oscillation ventilation (nHFOV) immediately after 
extubation reduces the paCO2 in comparison with nasal continuous positive airway pressure (nCPAP) 
at 72 hours after extubation in very low birth weight infants (VLBWs). 
 
Protocol/Methods 
1. Trial design 
Randomized controlled clinical trial of nHFOV versus nCPAP immediately after extubation. 
 
2. Participants 
Eligibility criteria 
 
Gestational age <32+0 weeks 
 
Birth weight <1500 g 
 
Received mechanical ventilation via an endotracheal tube for ≥120 h 
 
Caffeine treatment according to unit guidelines 
 
Arrival at the preset extubation criteria: 
o Time-cycled, pressure-controlled ventilation:  
PIP ≤22 cm H2O, PEEP ≤6 cm H2O,  
FiO2 25-40% to maintain SpO2 at 90-94%. 
paCO2 <65 mmHg with pH >7.2 
o Volume guarantee ventilation: 
Working Ppeak ≤22 cm H2O, PEEP ≤6 cm H2O 
FiO2 25-40% to maintain SpO2 at 90-94%. 
paCO2 <65 mmHg with pH >7.2 
o High frequency oscillation ventilation: set Pmean ≤12 cm H2O, Amplitude ≤30 cm 
H2O 
FiO2 25-40% to maintain SpO2 at 90-94%. 
paCO2 <65 mmHg with pH >7.2 
 
Decision of the attending clinician to extubate 
Exclusion criteria 
 
Major congenital malformation requiring surgery (e.g. esophageal atresia, diaphragmatic 
hernia, abdominal wall defect) 
 
Duct-dependent congenital heart disease 
 
Neuromuscular disease 
 
Participation in another RCT 
 
Death before reaching the eligibility criteria 
 
Hydrocortisone treatment at the time of enrolment 
 
Chronological age >28 days 
 
3. Study settings 

Two universitarian tertiary neonatal intensive care units in Berlin. 
 
4. Intervention 
Application of nHFOV or nCPAP immediately after extubation from endotracheal HFOV or from 
conventional ventilation. 
 
Equipment: 
o Devices used for endotracheal ventilation, nHFOV and nCPAP: Leoni Plus (Heinen 
und Löwenstein, Germany) or VN 500 (Dräger, Germany) 
o Interfaces: Endotracheal tubes (Vygon, France; Portex, Smiths Medical, UK) for 
endotracheal ventilation. Binasal prongs (Fisher & Paykel, New Zealand) for 
nHFOV and nCPAP. 
o Humidifier: MR 850 AGU (Fisher & Paykel, New Zealand) 
 
Primary intervention: 
o Extubation by withdrawing the endotracheal tube without sustained inflation 
o nHFOV group: immediately after extubation, apply nHFOV via binasal prongs. 
Set frequency at 10 Hz, I:E ratio 33:66, Amplitude 20 cm H2O, Pm 8 cm H2O, 
flow automatic (7 l/min). 
Set FiO2 to maintain SpO2 at 90-94%. 
o nCPAP group: immediately after extubation, apply nCPAP via binasal prongs. 
Set CPAP level at 8 cm H2O, flow 7 l/min. 
Set FiO2 to maintain SpO2 at 90-94%. 
 
Weaning of non-invasive respiratory support: 
o The weaning process is left to the discretion of the attending physician. 
o Once the infant is considered stable on nHFOV, intermittent or permanent weaning 
to nCPAP is allowed. 
o Once the infant is considered stable on nCPAP, intermittent or permanent weaning 
to high flow nasal cannula is allowed. 
 
Increasing non-invasive respiratory support: 
o Increasing non-invasive respiratory support is left to the discretion of the attending 
physician. The following settings are allowed in the nHFOV- and nCPAP-group, 
respectively. 
o nHFOV group: 
- Maximum amplitude 30 cm H2O, minimum frequency 9 Hz. 
- Maximum set Pmean 8 cm H2O. 
o nCPAP group: 
- Maximum CPAP level 8 cm H2O, maximum flow 8 l/min. 
 
Definition of treatment failure (infant meets at least one criterion): 
o Sustained pCO2 >80 mmHg and pH <7.20 confirmed by arterial or capillary blood 
gas analysis in spite of optimized non-invasive respiratory support with maximum 
settings as defined above. 
o FiO2 >0.6 to maintain SpO2 at 90-94% in spite of optimized non-invasive 
respiratory support with maximum settings as defined above. 
 
Reintubation: 
o Study patients may be intubated at any time due to clinical considerations (with or 
without reaching a criterion of “treatment failure”, as defined above). 
 
“Rescue-nHFOV” for infants in the nCPAP-group who “fail” nCPAP (defined as reaching a 
criterion of “treatment failure”, as defined above), but do not need immediate reintubation: 
o Trial of nHFOV via binasal prongs. 
o Choice of nHFOV settings are at the discretion of the attending clinician. 
 
“Rescue treatment” for infants in the nHFOV-group who “fail” nHFOV (defined as reaching 
a criterion of “treatment failure”, as defined above), but do not need immediate reintubation: 

o Choice of non-invasive respiratory support for the “rescue treatment” (e.g. nIPPV, 
nHFOV) and ventilator settings are at the discretion of the attending clinician. 
 
Planned data collection to document the respiratory support provided in the nCPAP- and the 
nHFOV-group: 
o Blood gas result before extubation (pH, paO2, paCO2 and BE). 
o Ventilator settings before extubation (mode and FiO2 in all patients; set Pmean during 
HFO; PIP and PEEP during time-cycled, pressure-controlled ventilation; working 
Ppeak and PEEP during volume guarantee ventilation). 
o Documentation of non-invasive respiratory support, including settings of nHFOV 
and/or nCPAP every 24h during the first 3 days after extubation and at 7 days after 
extubation (mode, set mean nHFOV pressure, frequency, amplitude; CPAP level; 
flow, FiO2), and after switch to “rescue treatment” or ”rescue-nHFOV”, if 
applicable. 
 
5. Outcomes 
 
Primary outcome: 
o paCO2 at 72 h (timeframe: 64 h to 80 h) after extubation 
 
Secondary outcomes: 
o pH, paO2, paCO2, BE at 2 h (timeframe: within first 6 h) after extubation 
o pH, paO2, BE at 72 h (timeframe: 64 h to 80 h) after extubation 
o Successful extubation (defined as spontaneous breathing in the assigned treatment 
group for ≥72h without being reintubated or reaching the criterion of “treatment 
failure”, as defined above) 
o Treatment failure (defined as reaching the criterion of “treatment failure”, as 
defined above, within the first 7 days after extubation) 
o Reintubation within the first 7 days after extubation 
o Adverse effects observed after extubation: documented episodes of airway 
obstruction due to highly viscous secretions, IVH III°-IV° (Papile), surgical NEC, 
pneumothorax, pulmonary interstitial emphysema, mild BPD (Jobe), PDA 
requiring surgical closure, ROP requiring laser treatment and/or injection of 
bevacizumab, PVL 
o Respiratory support: total duration of mechanical ventilation, total duration of 
supplemental oxygen, number of infants discharged with home oxygen 
 
Additional secondary outcomes for those infants who received “rescue treatment”: 
o pH, paO2, paCO2, BE at 2 h (timeframe: within first 6 h) after switch to “rescue” 
therapy 
o Successful rescue (defined as spontaneous breathing for ≥72h after starting 
“rescue” therapy, without reaching the criterion of “treatment failure”, as defined 
above) 
 
Follow-up study: 
o Lung function testing at 52 weeks’ corrected gestational age. 
 
6. Sample size 
Assuming a variability of the paCO2 as previously reported for difficult-to-wean preterm infants in 
our unit (Czernik C, J Matern Fetal Neonatal Med 2012) and a reintubation rate of 21% within 72 h 
after extubation, we calculated a sample size of 28 patients in each study arm to detect a difference 
in the paCO2 of 7 mmHg between the study groups, using a two-sided significance of 0.05 and a 
power of 0.8. 
 
 
 

7. Interim analyses and stopping guidelines 
An independent statistician performs an interim-analysis on the primary and secondary endpoints 
once 50% of the patients are randomized and outcome data is available. 
 
8. Randomization: sequence generation 
Sequence generation by an independent statistician and a study nurse. 
 
9. Randomization: type 
Block randomization using at least two different block sizes, stratification by center. 
 
10. Randomization: allocation concealment mechanism 
Sequentially numbered opaque sealed envelopes. Patients are randomized immediately before 
extubation. 
 
11. Registration of the trial 
clinicaltrials.gov 
 
 
Document dated 03-13-2012 
 
Document translated 01-15-2015