MANUSCRIPT CITATION

Manley BJ, Arnolda GRB, Wright IMR, Owen LS, Foster JP, Huang L, Roberts CT, Clark TL, Fan W-Q, Fang AYW, Marshall IR, Pszczola RJ, Davis PG, Buckmaster AG and the HUNTER Trial Investigators: Nasal High-Flow Therapy for Newborn Infants in Special Care Nurseries. New England Journal of Medicine 2019, 380(21):2031-2040. PMID: 31116919

REVIEWED BY

Yin Stein, MD
Fellow, Department of Pediatrics, Section of Neonatology
University of Colorado School of Medicine<

Robert M. Dietz, MD, PhD
Assistant Professor, Department of Pediatrics, Section of Neonatology
University of Colorado School of Medicine

TYPE OF INVESTIGATION

Treatment

QUESTION

Is high flow nasal cannula use in infants requiring non-invasive respiratory support, born at a gestational age of 31 weeks and higher and admitted to a special care nursery, non-inferior to continuous positive airway pressure by measure of treatment failure within 72 hours of randomization.

METHODS:

• Design: Prospective, multi-center, randomized-control trial
• Allocation: A computer-generated randomization sequence with variable block sizes was used.
• Blinding: Unblinded
• Follow-Up: Until hospital discharge, transfer to higher level of care or death
• Setting: 9 Australian non-tertiary centers, similar to level 2 special care nurseries as defined by the Committee on Fetus and Newborn of the American Academy of Pediatrics
•  Patients:
  •  Included:
    • 768 infants randomly assigned to a treatment group
      • 385 to HFNC group
      • 383 to CPAP group
    • 14 infants excluded did not meet eligibility criteria, did not consent or withdrew, therefore 754 were included in intention to treat analysis
    • Followed until hospital discharge or death
    • Born at gestational age 31 weeks 0 days or later
    • Had a birth weight of at least 1.2 kg
    • Less than 24 hours of age
    • Determined by treating clinician to require noninvasive respiratory support, receiving supplemental oxygen for more than 1 hr, or both
    • Less than 2 hours of existing CPAP treatment
  •  Excluded:
    • Greater than 2 hours of CPAP treatment
    • Had undergone endotracheal intubation
    • Had a known major congenital abnormality
    • If clinician determined that endotracheal intubation or transfer to a NICU was indicated
• Intervention: Eligible infants in the first 24 hours of life who required noninvasive respiratory support and were randomized to the high-flow group received an initial gas flow of 6 LPM with a maximal permissible gas flow of 8 LPM. Pre-specified criteria for treatment failure included the following:
  • FiO2 of greater than 0.4 for more than 1 hr to maintain target O2 sats of 91-95%
  • pH less than 7.2 with partial pressure of CO2 greater than 60 mmHg on an arterial or capillary blood obtained at least 1 hr after commencement of assigned treatment and obtained 1 hr apart
  • 2 or more episodes of apnea requiring positive pressure ventilation within 24 hr period or 6 or more episodes for which any intervention was indicated in a 6 hr period
  • Urgent need for endotracheal intubation
  • Urgent need for NICU transfer
• Outcomes:
  • Primary: Treatment failure within 72 hours after randomization, with non-inferiority defined as the upper limit of a two-sided 95% confidence interval for risk difference as less than 10 percentage points
  • Secondary: Reasons for treatment failure – endotracheal intubation; transfer to NICU; duration of respiratory support, supplemental oxygen and hospitalization; cost of care
• Analysis and Sample Size:
  • For the trial to have 90% power, a sample of 750 infants was required (one-sided alpha level of 0.025)
  • Primary intention-to-treat analysis and a secondary per-protocol analysis was performed, as recommended for non-inferiority trials
• Patient Follow-Up:
  • 1415 assessed for eligibility
    • 16 had > 2 hours of CPAP prior to starting
    • 60 previously were intubated
    • 11 had major congenital anomaly
    • 49 were transferred to NICU
  • 1310 met eligibility criteria
    • 295 had parents not approached for consent
    • 241 had parents who declined consent
  • 768 underwent randomization
    • 385 assigned to high flow group
    • 383 assigned to CPAP group

MAIN RESULTS:

Of the 768 neonates randomized:

Primary outcome: In the intention-to-treat analysis, treatment failure within 72 hours of randomization occurred in 78 of 381 (20.5%) infants randomly assigned to the high-flow therapy and 38 of 373 (10.2%) infants randomly assigned to CPAP. The risk difference between these therapies was 10.3% with a 95% confidence interval of 5.2 to 15.4.

Secondary outcome: In the intention-to-treat analysis, the most common reason for treatment failure in the two groups was an FiO2 of 0.4 for more than 1 hr. Treatment failure due to apnea occurred more frequently in the high-flow group than in the CPAP group. The most common other reason for treatment failure in the high-flow group was escalation of therapy in those infants who had not met the pre-specified treatment failure criteria. The only secondary outcomes for which there were 95% confidence intervals that did not cross zero were median hours of respiratory support after randomization (20 in high-flow group and 15 in CPAP group) and median hours of supplemental oxygen (5 in high-flow group and 1 in CPAP group).

CONCLUSION

These authors concluded, based on their findings, that high-flow nasal cannula treatment was not shown to be non-inferior to CPAP for preventing treatment failure within the first 72 hours after randomization for neonates admitted to a special care nursery requiring noninvasive respiratory support. Prior to starting their data collection, it was determined that high-flow therapy would be considered noninferior to CPAP if the upper limit of a two-sided 95% confidence interval for the risk difference was less than 10 percentage points. The risk difference in treatment failure between high-flow and CPAP was 10.3 percentage points, with the upper limit of the 95% confidence interval of 15.4.

COMMENTARY

Late preterm infants account for a significant majority of preterm infants born in the United States. According to the CDC, 70% of all preterm deliveries occur between 34 and 37 weeks gestational age. There is evidence to suggest that short-term morbidities, such as respiratory distress syndrome (RDS), are more prevalent in this population (1).  Non-invasive ventilation  (NIV) such as CPAP and humidified heated high flow nasal canula have been shown to be effective strategies for reducing RDS by optimizing pulmonary mechanics, reducing work of breathing and improving oxygenation and ventilation. Increasing use of NIV has reduced intubation in infants with RDS, likely due to the combination of positive airway distension and lack of de-recruitment alveoli and collapse of small airways during exhalation in the surfactant-deficient lung (2).

This noninferiority study of HFNC compared to CPAP by Manley and colleagues is the latest in a series of studies looking at NIV delivery in late preterm RDS. Use of CPAP is well-established as the standard of care for preterm infants with respiratory distress. Studies in a late preterm to term population of Cesarean-born infants demonstrated that prophylactic CPAP is helpful in reducing NICU admission by improving lung compliance and uniformity of lung compliance (2). High flow nasal cannula as an alternative has been demonstrated to have several advantages, including decreased nasal trauma (3) and has been shown in prior surveys to be preferred by parents of admitted infants (4). Despite the possible advantages of HFNC, the main drawback is the variability in pressures that can be generated, leading to possible “failure” of this mode of NIV.

Given that many infants of GA 31 weeks or greater are cared for in a non-tertiary NICU, the setting of this study in a similar environment enhances the generalizability of the results. In this setting, when comparing HFNC and CPAP with the goal of preventing respiratory failure, HFNC was shown to be inferior to CPAP, as defined by study parameters. Many of those who failed therapy on HFNC and transferred to CPAP ultimately stabilized, so that in the end, only slightly more than 5% in each group were intubated in the first 72 hours. Given that both groups had similar rates of treatment failure that ultimately required transfer to higher level care, it may be reasonable for centers to offer HFNC as an alternative to CPAP when requested by parents or staff, so long as CPAP is available on-site to rescue these infants should they fail HFNC.

REFERENCES

1. Consortium on Safe L, Hibbard JU, Wilkins I, et al. Respiratory morbidity in late preterm births. Jama. 2010; 304: 419-425.
2. Alexiou S, Panitch HB. Physiology of non-invasive respiratory support. Seminars in fetal & neonatal medicine. 2016; 21: 174-180.
3. Yoder BA, Stoddard RA, Li M, King J, Dirnberger DR, Abbasi S. Heated, Humidified High-Flow Nasal Cannula Versus Nasal CPAP for Respiratory Support in Neonates. Pediatrics. 2013; 131: e1482-e1490.
4. Klingenberg C, Pettersen M, Hansen EA, et al. Patient comfort during treatment with heated humidified high flow nasal cannulae versus nasal continuous positive airway pressure: a randomised cross-over trial. Arch Dis Child Fetal Neonatal Ed. 2014; 99: F134-137.