Nasal High-frequency Jet Ventilation (nHFJV) Following Extubation in Preterm Infants
Phase: NA
Conditions: Infant,Premature, Respiratory Failure, Respiratory Insufficiency, Respiratory Distress Syndrome in Premature Infant
Sponsor: University of Utah

Protocol version: 1.7; 3/4/2019 
Nasal high-frequency jet ventilation (nHFJV) following 
extubation in preterm infants 
 
Short title: Nasal high-frequency jet ventilation (nHFJV) 
Protocol version 1.7; 3/4/19 
 
 Jessica Davidson, Bradley A Yoder 
Division of Neonatology 
University of Utah School of Medicine 
 
 
 

Protocol version: 1.7; 3/4/2019 
A. Abstract 
This prospective, randomized trial involves extubating preterm infants from mechanical 
ventilation to nasal high-frequency jet ventilation (nHFJV) to assess whether this decreases the 
rates of reintubation compared to nasal intermittent positive pressure ventilation (NIPPV), which 
is currently a common practice. With this study, we aim to decrease the rates of reintubation 
and days requiring mechanical ventilation, which are both risk factors for bronchopulmonary 
dysplasia (BPD). Additionally, nHFJV may decrease rates of severe BPD, diagnosed at 36 
weeks corrected gestation age (CGA). 
B. Background 
Premature infants often experience respiratory insufficiency requiring increasing respiratory 
support, including endotracheal intubation and mechanical ventilation. The need for invasive 
mechanical ventilation as well as the duration of intubation are risk factors for BPD (Dumpa et 
al, 2011). Increasing efforts for early extubation to a non-invasive mode of support, such as 
continuous positive pressure ventilation (CPAP) or NIPPV, have been made. However, in these 
high risk preterm infants there remains a considerable rate of respiratory failure on CPAP 
requiring escalation in support, including reintubation (Barrington et al, 2001). Additionally, 
infants who have failed extubation experience higher rates of BPD and/or death (Manley et al, 
2016; Chawla et al, 2017).  
Use of non-invasive high frequency ventilation (HFV) has been described as a rescue method 
following failure of other non-invasive ventilator modes or as a means to increase the success 
post-extubation. When used as invasive high frequency ventilation, high frequency oscillatory 
ventilation (HFOV) or high frequency jet ventilation (HFJV) utilize supraphysiologic respiratory 
rates and small tidal volumes which has been show to inflict less lung injury than conventional 
modes of ventilation (Cotton et al, 2001). 

Protocol version: 1.7; 3/4/2019 
Using a mechanical newborn lung model, nasal HFV has improved CO2 removal when 
compared to conventional NIPPV (Mukerji et al, 2013; Mukerji et al, 2015). Animal studies in the 
lab of Kurt Albertine have shown improved ventilation and oxygenation in the high frequency 
nasal ventilation group versus the mechanical ventilation group in a preterm lamb model leading 
towards better alveolar formation noted histologically (Reyburn et al, 2008; Null et al, 2014). 
Few small clinical studies have looked at the use of nasal HFV however many were for short 
periods of time. Preterm infants on CPAP showed a significant decrease in pCO2 after being 
switched to nHFV for a two hour period (Colaizy et al, 2008). In a pilot trial investigating the use 
of nasal HFV immediately after extubation in high-risk preterm infants, it was noted that pCO2 
levels significantly decrease, although returned to pre-extubation values after discontinuing 
nasal HFV (Czernik et al, 2012). In a recent randomized controlled trial, 81 infants were 
randomized to nasal HFV or nasal CPAP following surfactant administration (Zhu et al, 2017). 
Infants in the nasal HFV group had a significantly decreased need for invasive mechanical 
ventilation compared to the nasal CPAP group, however their cohort had a mean gestation age 
of ~32 weeks (Zhu et al, 2017). None of these clinical studies noted any negative impact from 
using nasal HFV. 
 
C. Significance and Purpose 
Very low birth weight infants are at increased risk of requiring prolonged duration of mechanical 
ventilation and multiple intubations, both of which are risk factors for ventilator-induced lung 
injury and BPD. Thus, it is important to investigate respiratory support methods that are able to 
effectively oxygenate and ventilate these high risk preterm infants while reducing their risk of 
lung injury. Nasal high-frequency ventilation is one potential intervention that may decrease the 
risk of respiratory failure in very low birth weight infants. Small studies have shown effective 
respiratory support over short time periods in infants, however these studies use nasal high-

Protocol version: 1.7; 3/4/2019 
frequency oscillatory ventilation. To our knowledge there are no published studies looking at the 
use of nasal high-frequency jet ventilation in this high risk population. 
D. Hypothesis and Specific Aims 
We hypothesize that extubation of very preterm infants to nHFJV will significant decrease the 
rates of reintubation compared to those infants extubated to NIPPV. 
Our specific aims are: 
1. To examine the rate of respiratory failure requiring reintubation and invasive mechanical 
ventilation (IMV) within 72 hours of initiating study intervention. 
2. To examine the rate of respiratory failure requiring reintubation and IMV within 7 days of 
transitioning off of non-invasive study intervention 
3. To compare the total number of days requiring intubation with mechanical ventilation 
4. To compare the rates of moderate to severe BPD with and without altitude correction at 
36 weeks CGA per criteria defined by 2001 NICHD Consensus Conference 
 
E. Methods 
 
1. Trial design: This is a prospective, randomized trial. 
 
2. Study site: The study site will be the University of Utah Medical Center, a Level III 
neonatal intensive care unit with 52 beds. 
 
3. Population: Infants born 240/7 to 286/7 weeks gestational age (GA) requiring invasive 
mechanical ventilation (IMV) and meet extubation criteria within the first 7 days of life 
a. Inclusion criteria: 

Protocol version: 1.7; 3/4/2019 
i. 240/7 to 286/7 weeks GA 
ii. Intubated within 24 hours of life to synchronized intermittent 
mandatory ventilation (SIMV) or high frequency ventilation (HFV, 
includes HFOV or HFJV) 
iii. Meets unit guidelines for extubation within 7 days of life 
1. See Table 1 for outline of criteria 
iv. Infants intubated for surfactant replacement therapy via INSURE 
method (Intubation-Surfactant-Extubation) are eligible 
v. Initiation of treatment arm must occur within 6 hours of extubation 
1. If randomization occurs after the time of extubation, infants are 
eligible if FiO2 requirements are >30% 
vi. Consent obtained from parent/legal guardian 
b. Exclusion criteria: 
i. Major congenital and/or chromosomal anomalies 
ii. Upper oropharyngeal anomalies 
 
4. Randomization: 
a. Infants stratified by GA (240/7 – 256/7 weeks, 260/7 – 286/7 weeks) and 
randomized in blocks of 4 to nHFJV or NIPPV group 
b. Randomization and initiation of treatment arm must occur within 6 hours of 
extubation 
c. Randomization will occur via sealed opaque envelopes 
 
5. Intervention: Subjects will be randomized to be extubated to nasal HFJV (nHFJV) via 
the Bunnell Life Pulse high-frequency JET ventilator through a latex free PVC 
nasopharyngeal airway. 

Protocol version: 1.7; 3/4/2019 
a. Initial settings for nHFJV: 
i. PEEP = 8 
ii. HFJV PIP = 25 
iii. On-time = 0.034 second 
iv. Rate = 360 breaths per minute 
v. Conventional rate = 10 breaths per minute 
vi. I-time = 1 second 
vii. Conventional PIP = 24 
viii. FiO2 adjusted to maintain target saturations per unit guidelines 
b. Available sizes of nasopharyngeal airway are 12 Fr and 14 Fr with an internal 
diameter of 3.0 mm and 3.5 mm, respectively, which will be attached to a 3.0 
mm LifePort endotracheal tube adapter 
 
6. Control group: Randomized subjects will be extubated to non-invasive positive 
pressure (NIPPV) via Hudson prongs. 
a. Initial settings 
b. PIP = 25 
c. PEEP = 6 
d. Ti = 0.6 sec 
e. Rate = 20 breaths per minute 
f. 
FiO2 adjusted to maintain target saturations per unit guidelines 
g. Infants in the control group must remain on the Hudson prong interface for a 
minimum of 72 hours. At that time, can be transitioned to another interface to 
deliver NIPPV at the discretion of the medical team. 
 
7. Data to be collected: 

Protocol version: 1.7; 3/4/2019 
a. Specific Aim 1: To examine the rate of respiratory failure requiring 
reintubation and IMV within 72 hours of initiating study intervention. 
i. Reintubation criteria: 
1. Respiratory acidosis with pH <7.2 and PaCO2 >60 mmHg on 2 
successive blood gases on optimal ventilatory settings 
2. FiO2 >0.6 to maintain SpO2 >88% for >1 hour 
3. Impending respiratory failure noted by Silverman score >6 
1. Silverman, W. and Anderson, D.: Pediatrics 17:1, 1956. 
2. Depiction of scoring system noted in Figure 1. 
4. Severe/worsening apnea and bradycardia 
1. >3 episodes per hour requiring stimulation OR  
2. >1 episode of apnea requiring bag-mask ventilation in 
24 hours 
b. Specific Aim 2: To examine the rate of respiratory failure requiring 
reintubation and IMV within 7 days of transitioning off of non-invasive study 
intervention. 
c. Specific Aim 3: To compare the total number of days of intubation with 
mechanical ventilation in the two study arms 
d. Specific Aim 4: To compare rates of moderate to severe BPD with and 
without altitude correction at 36 weeks CGA per criteria defined by 2001 
NICHD Consensus Conference 
 
8. Procedure/Protocol 
a. Identify infants meeting inclusion criteria within the first 24 hours of life 

Protocol version: 1.7; 3/4/2019 
i. If infant meets extubation criteria within the first 7 days of life, 
approach care provider for permission to obtain consent from 
parents/legal guardian 
1. Record patient and maternal demographic information. 
b. Ensure standard of care transcutaneous monitor (TCM) is placed prior to 
initiation of study intervention 
i. Blood gases ordered per clinical practice 
c. Randomized infants extubated to nHFJV or NIPPV 
i. Nasopharyngeal airway to be replaced in alternating nares every 48 
hours to decrease risk of skin breakdown 
d. Respiratory settings adjusted to maintain target blood gas and/or TCM values 
i. Goal: pH >7.2, PaCO2 45-60 mmHg, PaO2 60-80 mmHg 
ii. Adjustment of nHFJV support as indicated in Table 2 
iii. Adjustment of NIPPV support as indicated in Table 3 
e. Record vital signs (heart rate, respiratory rate, blood pressure) and ventilator 
support, including FiO2, TCM/PaCO2 and Silverman score for the first 24 
hours of study support as follows: every 1 hour for three recordings then 
every 3 hours for three recordings and then every 6 hours for two recordings. 
Subsequently we will record this data every 12 hours until 48 hours and then 
every 24 hours for the remaining 7 days of the study period. 
f. 
Infant can be transitioned to CPAP via binasal prongs and/or mask when on 
minimal settings of the respiratory intervention for > 24 hours with acceptable 
oxygen saturations and TCM 
i. Minimal nHFJV settings 
1. PEEP of 6, IMV rate of 0, HFJV PIP of 15, HFJV rate of 360 
breaths per min, FiO2 < 0.3 

Protocol version: 1.7; 3/4/2019 
2. Transition to CPAP of 6 cm H2O 
ii. Minimal NIPPV settings 
1. PEEP of 5, PIP of 15, rate of 5 breaths per minute 
2. Transition to CPAP of 6 cm H2O 
iii. At the discretion of the attending physician, infant can be placed on 
bubble CPAP (bCPAP) or ventilator-interface CPAP. 
g. Criteria for termination of non-invasive study mode: 
i. Respiratory failure meeting reintubation criteria as noted above 
ii. At the request of the attending physician and/or parent/legal guardian 
iii. Upon transfer of infant to Primary Children’s Hospital for non-
respiratory medical/surgical care 
h. Continue study respiratory intervention for 7 days, after which the respiratory 
support will be transitioned from nHFJV to another respiratory support 
modality of the attending physicians choosing. 
 
9. Statistical Analysis: Data will be de-identified and analyzed on an intent to treat basis. 
Statistical analysis will be performed using SPSS (version 25, IBM, Armonk, NY). The 
primary outcome and other categorical measures will be analyzed by Chi-square or 
Fisher’s Exact test. Student’s t test will be used for analysis of normally distributed 
continuous data and Mann-Whitney U test will be applied for ordinal data or continuous 
data that is not normally distributed. Two-sided P values of less than 0.05 will be 
considered to indicate statistical significance, and no adjustments will be made for 
multiple comparisons 
 
10. Population and Recruitment Time: 

Protocol version: 1.7; 3/4/2019 
a. Approximately 60 infants born 24 0/7 to 28 6/7 weeks GA are born at the UUMC 
NICU each year 
i. Estimated sample size is 40 infants (n=20 per group)This is a pilot 
study designed to test feasibility and safety of the nHFJV. However, 
the sample size proposed may allow identification of possible 
significant benefits. Based on historical failure rates in this patient 
population, including a recent study from Zhu et al, the estimated 
failure approaches 50% with the current standard. If we were able to 
show a reduction in that failure rate by 50% (from 50% to 25%, as 
shown in the Zhu, et al study) we would approach a P value of 0.05 by 
Chi-squared analysis. 
1. Zhu X-W, et al. Pediatric Pulmonology, 2017; 52(8)  
b. Expected time to complete study from initiation through closeout is approximately 
2 years. 
 
F. Risks and Benefits 
NIPPV is a routine and well known mode of respiratory support with a few known risks, including 
air leaks, gaseous distension/discomfort and skin breakdown at the site of the prongs/mask. 
Effort is made to decrease the gaseous distension by allowing the enteric tube placed for 
enteral feeds to vent periodically throughout the day. We do not anticipate higher risk in the 
patients randomized to the nHFJV group. The nasopharyngeal airway will be replaced in 
alternating nares in the nHFJV group every 48 hours to decrease the risk of skin breakdown.  
Potential benefits to study participants assigned to the nHFJV group may include decreased risk 
of reintubation and decreased days requiring mechanical ventilation. This improvement may 
translate to decreased severity of BPD at 36 weeks CGA. Benefits to society include increased 

Protocol version: 1.7; 3/4/2019 
knowledge in a novel mode of respiratory support that may aid in quicker extubation and as a 
rescue mode of respiratory support to prevent intubation and mechanical ventilation. This 
potential for reduced severity of BPD could shorten hospital stays and decrease subsequent 
medical costs associated with care for severe BPD. 
 
G.  References 
1. Colaizy TT, Younis UMM, Bell EF, Klein JM. Nasal high-frequency ventilation for 
premature infants. Acta Paediatrica. 2008; 97:1518-1522. 
2. Zhu X-W, Zhao J-N, Tang S-F, Yan J, Shi Y. Noninvasive high-frequency oscillatory 
ventilation versus nasal continuous positive airway pressure in preterm infants with 
moderate-severe respiratory distress syndrome: a preliminary report. Pediatric 
Pulmonology. 2017;52(8): 1038-1042. 
3. Czernik C, Schmalisch G, Buhrer C, Proquitte H. Weaning of neonates from mechanical 
ventilation by use of nasopharyngeal high-frequency oscillatory ventilation: a preliminary 
study. Journal of Maternal-Fetal & Neonatal Medicine. 2012; 25(4):374-378. 
4. Mukerji A, Finelli M, Belik J. Nasal high-frequency oscillation for lung carbon dioxide 
clearance in the newborn. Neonatology. 2013; 103:161-165. 
5. Mukerji A, Belik J. Neonatal nasal intermittent positive pressure ventilation efficacy and 
lung pressure transmission. Journal of Perinatology. 2015; 35:716-719. 
6. Null DM, Alvord J, Leavitt W, Wint A, Dahl MJ, Presson AP, et al. High frequency nasal 
ventilation for 21 days maintains gas exchange with lower respiratory pressures and 
promotes alveolarization in preterm lambs. Pediatr Res. 2014; 75(4):507-516. 
7. Chawla S, Natarajan G, Shankaran S, Carper B, Brion LP, Keszler M et al. Markers of 
successful extubation in extremely preterm infants, and morbidity after failed extubation. 
Journal of Pediatrics. 2017; 189:113-119. 
8. Manley BJ, Doyle LW, Owen LS, Davis PG. Extubating extremely preterm infants: 
predictors of success and outcomes following failure. Journal of Pediatrics. 2016; 
173:45-49. 
9. Barrington KJ, Bull D, Finer NN. Randomized trial of nasal synchronized intermittent 
mandatory ventilation compared with continuous positive airway pressure after 
extubation of very low birth weight infants. Pediatrics. 2001; 107(4):638-641. 
10. Dumpa V, Northrup V, Bhandari V. Type and timing of ventilation in the first postnatal 
week is associated with bronchopulmonary dysplasia/death. American Journal of 
Perinatology. 2011; 28(4):321-329. 
11. Reyburn B, Li M, Metcalfe DB, Kroll NJ, Alvord J, Wint A, et al. Nasal ventilation alters 
mesenchymal cell turnover and improves alveolarization in preterm lambs. American 
Journal of Respiratory and Critical Care Medicine. 2008; 178:407-418. 
12. Cotton M, Clark RH. The science of neonatal high-frequency ventilation. Respiratory 
Care Clinics of North America. 2001; 7(4):611-631. 
13. Jobe AH, Bancalari E. Bronchopulmonary dysplasia. American Journal of Respiratory 
and Critical Care Medicine. 2001; 163(7):1723-1729. 

Protocol version: 1.7; 3/4/2019 
14. Silverman WA, Andersen DH. A controlled clinical trial of effects of water mist on 
obstructive respiratory signs, death rate and necropsy findings among premature infants. 
Pediatrics. 1956; 1(17) 
 
 
 

Protocol version: 1.7; 3/4/2019 
Table 1. Unit guidelines for extubation criteria 
 
 
 
WEIGHT (grams) 
 
 
 
< 1000 
1000-2000 
2000-3000 
> 3000 
MAP 
8 
9-10 
10-12 
12 
Amp 
16 
18 
20 
22 
FiO2 
< 0.4 
HFOV 
 
 
 
WEIGHT (grams) 
 
 
 
< 1000 
1000-2000 
2000-3000 
> 3000 
PIP 
< 16 
16-20 
20 
PEEP 
< 6 
< 7 
< 8 
PS 
< 6 – 8 
FiO2 
< 0.4 
Rate 
16 – 20 
PC-SIMV and PC-PSV 
 
 
 
WEIGHT (grams) 
 
 
 
< 1000 
1000-2000 
2000-3000 
> 3000 
PIP 
< 16 
16-20 
20 
PEEP 
< 6 
< 7 
< 8 
VT 
4 – 5 ml/kg 
PS 
< 6 – 8 
FiO2 
< 0.4 
Rate 
16 – 20 
SIMV + VG and PSV + VG 
 
 
 

Protocol version: 1.7; 3/4/2019 
Table 2a. Adjustment of nHFJV support 
 
                                           In order of preference: 
Improving PaO2 
1. Wean FiO2 until < 0.3 
2. Wean PEEP by 1 cm H20 to a minimum of 6 
Improving PaCO2 
1. Wean IMV PIP by 1-2 every 3-4 hours to a 
minimum of 15 cm H2O 
2. Wean IMV rate by 2 every 3-4 hours to off 
3. Wean HFJV PIP by 1-2 every 3-4 hours to 
minimum of 15 cm H2O 
Worsening PaO2 and FiO2 > 0.4 
1. Increase PEEP by 1-2 cm H2O every 15 
minutes to maximum of 12 cm H2O 
2. If no chest rise with IMV breaths, increase 
IMV PIP by 1-2 cm H2O to a maximum of 30 
cm H2O 
Worsening PaCO2 
1. Increase HFJV PIP by 2-3 cm H2O until visible 
chest wiggle to maximum of 30 cm H2O 
2. If no effect, increase HFJV rate by 60 bpm to 
maximum of 480 bpm 
3. If no effect, increase IMV PIP by 1-2 cm H2O 
every 30-60 minutes to maximum of 30 cm 
H2O 
4. If no effect, increase IMV rate by 1-2 bpm to 
maximum of 20 bpm 
 
Table 2b. Caveats of care with nHFJV support 
 
1) IMV PIP should remain at least 1-2 below the nHFJV PIP so conventional 
breaths do not interrupt HFJV. Listen to infants’ breaths and adjust as 
needed. 
2) If receiving “cannot meet ready conditions” alarm, decrease the IMV 
breaths until the alarm stops and then increase IMV breaths to goal 
3) Set/keep “slope” on Drager IMV breaths to 0.0 
4) If increasing stomach gas, can consider weaning nHFJV PIP by 1-2 to 
minimum of 16 cmH2O 
5) Can increase nHFJV PIP by 1-2 if lower levels activate “low PIP” alarm 
6) If PAW reaches 12 cm H2O, recommend obtaining chest x-ray 
7) Air trapping related to inadequate high frequency expiratory time or 
excessive nHFJV PIP should not occur due to the non-invasive approach 
 
 

Protocol version: 1.7; 3/4/2019 
Table 3. Adjustment of NIPPV support 
 
                                           In order of preference: 
Improving PaO2 
1. Wean FiO2 until < 0.3 
2. Wean PEEP by 1 to a minimum of 5 cm H20 
Improving PaCO2 
1. Wean PIP by 1-2 every 3-4 hours to a 
minimum of 15 cm H2O 
2. Wean rate by 5 every 3-4 hours to minimum 
of 5 bpm 
Worsening PaO2 and FiO2 > 0.4 
1. Increase PEEP by 1-2 cm H2O every 15 
minutes to maximum of 10 cm H2O 
Worsening PaCO2 
1. Increase PIP by 2-3 cm H2O to maximum of 
30 cm H2O 
2. Increase rate by 5 to maximum of 30 bpm 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Protocol version: 1.7; 3/4/2019 
Figure 1. Silverman Scoring system for respiratory failure