MANUSCRIPT CITATION

Zhu X, Qi H, Feng Z, Shi Y, De Luca D; Nasal Oscillation Post-Extubation (NASONE) Study Group. Noninvasive High-Frequency Oscillatory Ventilation vs Nasal Continuous Positive Airway Pressure vs Nasal Intermittent Positive Pressure Ventilation as Postextubation Support for Preterm Neonates in China: A Randomized Clinical Trial. JAMA Pediatr. 2022 Jun 1;176(6):551-559. PMID: 35467744

REVIEWED BY

Faeq Almudares MD MS
Assistant Professor of Pediatrics
Department of Pediatrics, Baylor College of Medicine/Division of Neonatology, Texas Children’s Hospital
almudare@bcm.edu

Bheru Gandhi MD
Assistant Professor of Pediatrics
Department of Pediatrics, Baylor College of Medicine/Division of Neonatology, Texas Children’s Hospital

TYPE OF INVESTIGATION

Randomized Control Trial

QUESTION

(P) Among preterm infants born between 25 0/7 and 32 6/7-week gestation,

(I/C) does noninvasive high-frequency oscillatory ventilation (NHFOV)when compared to nasal continuous positive airway pressure (NCPAP) and nasal intermittent positive pressure ventilation (NIPPV)

(O) prove more effective in reducing invasive mechanical ventilation duration and the need for reintubation

(T) after first extubation until the time of discharge.

METHODS:

• Design: Multicenter, three-arms, superiority, Randomized control trial
• Allocation: Centralized randomization, and investigators were concealed. Subjects were not allowed to cross over after randomization. Twins were allocated in the same treatment group.
• Blinding: But the outcome assessors (research nurses or local investigators) and the investigators performing the final statistical analyses were blinded to treatment allocation.
• Follow-up period: Until time of discharge.
• Setting: Multicenter study, included 69 tertiary referral NICUs in China.
• Patients:
  • Admitted to the NICU between December 2017 to May 2021
  • Inclusion criteria:
    • Born between 25 0/7 and 32 6/7-week gestation.
    • Received invasive mechanical ventilation.
    • Fulfill predetermined extubation readiness criteria.
  • Exclusion criteria:
    • Birth weight less than 600 gm.
    • Never received invasive mechanical ventilation.
    • Received invasive mechanical ventilator but never extubated
    • Neonates with major congenital or chromosomal anomalies, neuromuscular disease, upper respiratory tract abnormalities, requiring surgery prior to the first extubation, grade 4 intraventricular hemorrhage, congenital lung disease or malformation.
  • Intervention:
    • Group 1: NCPAP with an initial pressure of 5 cm H2O. Pressure ranges of 3-8.
    • Group 2: NIPPV with initial settings of positive end-expiratory pressure (PEEP) of 4 cm H2O, Peak expiratory pressure of 15 cm H2O, respiratory rate (RR) of 30 breaths per minute. Inspiratory time (iT) of 0.45-0.5 sec. Settings ranges: PEEP of 4-8, PIP of 15-25, RR of 30-50
    • Group 3: NHFOV with initial settings of mean airway pressure (Paw) 10, inspiratory time (iT) 50% (1:1), frequency 10 Hz, Amplitude 25 cm H2O. Settings ranges: Paw of 5-16, Frequency 8-15, Amplitude 25-50.
    • Neonates were re-intubated due to respiratory acidosis (pH <7.2), hypoxia while on FiO2 0.4, severe apnea, pulmonary hemorrhage, severe respiratory distress, hemodynamic instability or cardio-respiratory arrest.
  • Outcomes:
    • The primary outcomes focused on the need of invasive mechanical ventilation regarding: (i) duration, (ii) ventilator-free days and (iii) the need for re-intubation.
  • Analysis and Sample Size:
    • Intension-to-treat analysis was performed.
    • Interim analysis was performed at 50% enrollment without safety concerns.
    • Statistical significance was set at two-sided P <0.05.
    • Sample size of 480 neonates per group (total = 1440) was calculated for an alpha = 0.05, beta= 95%, and a reduction rate of 20% in invasive mechanical ventilation based on prior studies. The trial’s sample size was calculated, using a lower estimated reduction rate than the reported rates from prior published studies (approximately 30%).
    • The trial was completed without safety concerns or protocol deviations/modifications.
    • Dichotomous outcome were represented as risk difference with 95% confidence interval, and chi-square was utilized
    • Continuous outcomes were represented as mean or median differences, and parametric and non-parametric tests were used according to the data.
    • Analysis was performed using SPSS, version 16.
    • Data analysis was performed blindly to the treatment allocation.

• Patient follow-up: A total number of 1974 neonates were assessed for eligibility. A total number of neonates underwent randomization were 1493, 53 patients were withdrawn from the study per parental request. Total number of 1440 were included in the analysis.

MAIN RESULTS

Table 1. Baseline characteristics of the cohort

The table 1 shows a selected baseline characteristics of the study population were shown on the table above. Neonates born between 25- to 28-week gestation represented 13-16% of each group. Race and ethnicity data was not collected, as all the study participants were Chinese neonates.

Neonates allocated to the NHFOV had fewer days on invasive mechanical ventilation compared to those on NCPAP and NIPPV. The NCPAP group had higher re-intubation rate than NIPPV and NHFOV, with no significant differences were observed between the latter two. Additionally, the NIPPV group had more ventilator-free days that the NCPAP group, with no significant difference compared to the NHFOV group.

The intervention groups didn’t differ significantly based on the reported secondary outcomes including rate of bronchopulmonary dysplasia, mortality rate, intraventricular hemorrhage, necrotizing enterocolitis, hemodynamically significant patent ductus arteriosus, and duration of oxygen supplementation. Although, the postnatal steroid use was noticed to be lower in the NHFOV group when compared to NCPAP, but no difference was observed when compared to the NIPPV.

Regarding overall safety, no significant differences were observed between the groups, except for weight gain in favor of NHFOV compared to NCPAP. The other reported safety outcomes were rates of vomiting, air leaks and apneas, volume of gastric residual, weight gain, nasal skin injury and pain profile score, all showed no significant differences.

CONCLUSION:

NHFOV use post-extubation reduces the duration of invasive mechanical ventilation when compared to NCPAP and NIPPV, and it results in lower rate of re-intubation than NCPAP. NHFOV use after extubation is a safe mode of ventilation compared to the more commonly used mode of respiratory supports NCPAP and NIPPV. No significant differences were observed regarding overall outcome including mortality, BPD, IVH or ROP.

COMMENTARY:

Invasive mechanical ventilation (IMV) while life-saving in neonates with severe respiratory failure, is often associated with worsened neonatal outcomes, including bronchopulmonary dysplasia (BPD), lower neurodevelopmental scores, and death [1]. In order to reduce complications of IMV, various non-invasive ventilation (NIV) strategies have been studied to evaluate improvement in extubation success. Nasal high-frequency oscillatory ventilation (NHFOV) is a newer NIV mode. NHFOV generates high mean airway pressure with superimposed oscillations, thus decreasing air trapping seen with high nasal continuous positive airway pressure (NCPAP) pressures [2]. It can also eliminate the need for synchronization with nasal intermittent positive pressure ventilation (NIPPV)[2].

 

The NASONE (Nasal Oscillation Post-Extubation) study is the largest randomized control trial to assess NHFOV’s superiority over NCPAP in preventing reintubation and reducing IMV duration. NHFOV’s effectiveness was not significantly different than NIPPV [3]. This study was unique in its direct comparison of the three NIV modes: NHFOV, NCPAP and NIPPV. It was well designed and adequately powered to investigate the primary outcomes. Its design enhances that generalizability of the approach, although the effectiveness of the intervention may vary in certain patient populations. The analysis was conducted via an intention-to-treat basis, with no crossover between groups permitted. However, in clinical practice, different NIV modes may be attempted before intubation.

 

Although NHFOV showed greater effectiveness than NCPAP in preventing re-intubation, it did not impact BPD incidence. Using a pragmatic approach with a range of gestational ages, the paper assumes 31-32 week infants would have the same severity of lung disease as 25-26-week infants, and that NHFOV would have a similar effect. Upon limiting the analysis to extremely premature neonates or infants with severe respiratory failure, the secondary analysis showed NHFOV was associated with decreased incidence of moderate to severe BPD [4].

 

Limitations include lack of diversity in ethnicity and racial backgrounds of the cohort, and the absence of NIPPV synchronization. Given the overall limited availability of NIPPV synchronization, the study’s approach was appropriate. The lower rates of antenatal steroid use in the study cohort may have influenced the measured outcomes, but those rates were similar between intervention groups. Nevertheless, caution is needed when implementing the trial results in different hospitals and regions.

 

There were no reported adverse outcomes associated with higher pressures experienced by neonates in the NHFOV group compared to the NCPAP and NIPPV groups. This aligns with previously reported results [5]. However, it is important to acknowledge that assessment of feeding intolerance was limited and did not include the rates of feeding interruptions or abdominal distension. Nonetheless, infants in the NHFOV group had statistically significant higher weight gain than the NCPAP group. The difference in weight gain, 13 gm vs 12 gm, maybe clinically insignificant but does show that HFOV did not compromise growth.

 

This trial contributes to the evidence supporting the efficacy and safety of NHFOV in preterm infants, underscoring its potential advantages over NCPAP [6, 7]. Further trials are warranted to confirm the short-term benefits of NHFOV and to investigate its long-term efficacy and safety in preterm infants.

FUNDING

Public Chinese research program – Scientific Research Projects Unit of Chongqing Medical University (grant cstc2016shms-ztzx13001).

CONFLICTS OF INTEREST

Conflict of interest was reported in the publication. The principal investigator, Dr. De Luca received supports from Vyaire Medical, Getings, and Philips.

REFERENCES

1. Miller JD, Carlo WA. Pulmonary complications of mechanical ventilation in neonates. Clin Perinatol. 2008 Mar;35(1):273-81, x-xi.
2. De Luca D, Dell’Orto V. Non-invasive high-frequency oscillatory ventilation in neonates: review of physiology, biology and clinical data. Arch Dis Child Fetal Neonatal Ed. 2016 Nov;101(6):F565-f70.
3. Zhu X, Qi H, Feng Z, Shi Y, De Luca D. Noninvasive High-Frequency Oscillatory Ventilation vs Nasal Continuous Positive Airway Pressure vs Nasal Intermittent Positive Pressure Ventilation as Postextubation Support for Preterm Neonates in China: A Randomized Clinical Trial. JAMA Pediatr. 2022 Jun 1;176(6):551-59.
4. Zhu X, Li F, Shi Y, Feng Z, De Luca D. Effectiveness of Nasal Continuous Positive Airway Pressure vs Nasal Intermittent Positive Pressure Ventilation vs Noninvasive High-Frequency Oscillatory Ventilation as Support After Extubation of Neonates Born Extremely Preterm or With More Severe Respiratory Failure: A Secondary Analysis of a Randomized Clinical Trial. JAMA Netw Open. 2023 Jul 3;6(7):e2321644.
5. Seth S, Saha B, Saha AK, Mukherjee S, Hazra A. Nasal HFOV versus nasal IPPV as a post-extubation respiratory support in preterm infants-a randomised controlled trial. Eur J Pediatr. 2021 Oct;180(10):3151-60.
6. Chen L, Wang L, Ma J, Feng Z, Li J, Shi Y. Nasal High-Frequency Oscillatory Ventilation in Preterm Infants With Respiratory Distress Syndrome and ARDS After Extubation: A Randomized Controlled Trial. Chest. 2019 Apr;155(4):740-48.
7. Iranpour R, Armanian AM, Abedi AR, Farajzadegan Z. Nasal high-frequency oscillatory ventilation (nHFOV) versus nasal continuous positive airway pressure (NCPAP) as an initial therapy for respiratory distress syndrome (RDS) in preterm and near-term infants. BMJ Paediatr Open. 2019;3(1):e000443.