Hodgson Et Al-2023-Cochrane Database of Systematic Reviews

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Cochrane Database of Systematic Reviews
Nasal high flow therapy for primary respiratory support in preterm

infants (Review)
Hodgson KA, Wilkinson D, De Paoli AG, Manley BJ
Hodgson KA, Wilkinson D, De Paoli AG, Manley BJ.

Nasal high flow therapy for primary respiratory support in preterm infants.
Cochrane Database of Systematic Reviews 2023, Issue 5. Art. No.: CD006405.
DOI: 10.1002/14651858.CD006405.pub4.
www.cochranelibrary.com
Nasal high flow therapy for primary respiratory support in preterm infants (Review)
Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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TABLE OF CONTENTS
ABSTRACT..................................................................................................................................................................................................... 1
PLAIN LANGUAGE SUMMARY....................................................................................................................................................................... 2
SUMMARY OF FINDINGS.............................................................................................................................................................................. 4
BACKGROUND.............................................................................................................................................................................................. 8
OBJECTIVES.................................................................................................................................................................................................. 9
METHODS..................................................................................................................................................................................................... 9
Figure 1.................................................................................................................................................................................................. 11
RESULTS........................................................................................................................................................................................................ 13
Figure 2.................................................................................................................................................................................................. 16
Figure 3.................................................................................................................................................................................................. 17
DISCUSSION.................................................................................................................................................................................................. 20
AUTHORS' CONCLUSIONS........................................................................................................................................................................... 21
ACKNOWLEDGEMENTS................................................................................................................................................................................ 22
REFERENCES................................................................................................................................................................................................ 23
CHARACTERISTICS OF STUDIES.................................................................................................................................................................. 29
DATA AND ANALYSES.................................................................................................................................................................................... 58
Analysis 1.1. Comparison 1: Nasal high flow (nHF) compared with continuous positive airway pressure (CPAP) for primary 61
respiratory support in preterm infants, Outcome 1: Death or bronchopulmonary dysplasia..........................................................
respiratory support in preterm infants, Outcome 2: Death................................................................................................................
respiratory support in preterm infants, Outcome 3: Bronchopulmonary dysplasia.........................................................................
respiratory support in preterm infants, Outcome 4: Treatment failure within 72 hours of trial entry.............................................
respiratory support in preterm infants, Outcome 5: Mechanical ventilation within 72 hours of trial entry....................................
respiratory support in preterm infants, Outcome 6: Mechanical ventilation at any time point after trial entry.............................
respiratory support in preterm infants, Outcome 7: Duration of any respiratory support (days)....................................................
respiratory support in preterm infants, Outcome 8: Duration of supplemental oxygen (days).......................................................
respiratory support in preterm infants, Outcome 9: Surfactant treatment......................................................................................
respiratory support in preterm infants, Outcome 10: Duration of hospitalisation (days)................................................................
respiratory support in preterm infants, Outcome 11: Pneumothorax...............................................................................................
respiratory support in preterm infants, Outcome 12: Nasal trauma.................................................................................................
respiratory support in preterm infants, Outcome 13: Nosocomial sepsis.........................................................................................
respiratory support in preterm infants, Outcome 14: Gastrointestinal perforation or severe necrotising enterocolitis.................
respiratory support in preterm infants, Outcome 15: Time to full feeds (days)................................................................................
respiratory support in preterm infants, Outcome 16: Retinopathy of prematurity..........................................................................
respiratory support in preterm infants, Outcome 17: Subgroup analysis – mechanical ventilation with or without surfactant
permitted...............................................................................................................................................................................................
respiratory support in preterm infants, Outcome 18: Subgroup analysis – pneumothorax with or without surfactant permitted...
Nasal high flow therapy for primary respiratory support in preterm infants (Review) i
Informed decisions.
respiratory support in preterm infants, Outcome 19: Subgroup analysis – mechanical ventilation with or without second-line
CPAP permitted.....................................................................................................................................................................................
Analysis 2.1. Comparison 2: Nasal high flow (nHF) compared with nasal intermittent positive pressure ventilation (NIPPV) for 76
primary respiratory support in preterm infants, Outcome 1: Death or bronchopulmonary dysplasia............................................
primary respiratory support in preterm infants, Outcome 2: Death.................................................................................................
primary respiratory support in preterm infants, Outcome 3: Bronchopulmonary dysplasia...........................................................
primary respiratory support in preterm infants, Outcome 4: Treatment failure within 72 hours of trial entry...............................
primary respiratory support in preterm infants, Outcome 5: Mechanical ventilation within 72 hours of trial entry......................
primary respiratory support in preterm infants, Outcome 6: Mechanical ventilation at any time point after trial entry...............
primary respiratory support in preterm infants, Outcome 7: Surfactant treatment........................................................................
primary respiratory support in preterm infants, Outcome 8: Duration of hospitalisation (days)....................................................
primary respiratory support in preterm infants, Outcome 9: Pneumothorax...................................................................................
primary respiratory support in preterm infants, Outcome 10: Nasal trauma...................................................................................
primary respiratory support in preterm infants, Outcome 11: Nosocomial sepsis...........................................................................
primary respiratory support in preterm infants, Outcome 12: Gastrointestinal perforation or severe necrotising enterocolitis.....
primary respiratory support in preterm infants, Outcome 13: Time to full feeds (days)..................................................................
primary respiratory support in preterm infants, Outcome 14: Duration of respiratory support (days)...........................................
primary respiratory support in preterm infants, Outcome 15: Duration of supplemental oxygen (days).......................................
APPENDICES................................................................................................................................................................................................. 83
WHAT'S NEW................................................................................................................................................................................................. 87
HISTORY........................................................................................................................................................................................................ 87
CONTRIBUTIONS OF AUTHORS................................................................................................................................................................... 88
DECLARATIONS OF INTEREST..................................................................................................................................................................... 88
SOURCES OF SUPPORT............................................................................................................................................................................... 88
DIFFERENCES BETWEEN PROTOCOL AND REVIEW.................................................................................................................................... 89
INDEX TERMS............................................................................................................................................................................................... 90
Nasal high flow therapy for primary respiratory support in preterm infants (Review) ii
Informed decisions.
[Intervention Review]
Nasal high flow therapy for primary respiratory support in preterm

infants
Kate A Hodgson1,2, Dominic Wilkinson3,4, Antonio G De Paoli5, Brett J Manley1,2
1Women's Newborn Research Centre, The Royal Women's Hospital, Parkville, Australia. 2Department of Obstetrics and Gynaecology,
University of Melbourne, Melbourne, Australia. 3Oxford Uehiro Centre for Practical Ethics, University of Oxford, Oxford, UK. 4Robinson
Research Institute, University of Adelaide, Adelaide, Australia. 5Department of Paediatrics, Royal Hobart Hospital, Hobart, Australia
Contact: Kate A Hodgson, kate.hodgson@thewomens.org.au.
Editorial group: Cochrane Neonatal Group.

Publication status and date: New search for studies and content updated (conclusions changed), published in Issue 5, 2023.
Citation: Hodgson KA, Wilkinson D, De Paoli AG, Manley BJ. Nasal high flow therapy for primary respiratory support in preterm infants.
Cochrane Database of Systematic Reviews 2023, Issue 5. Art. No.: CD006405. DOI: 10.1002/14651858.CD006405.pub4.
ABSTRACT
Background
Nasal high flow (nHF) therapy provides heated, humidified air and oxygen via two small nasal prongs, at gas flows of more than 1 litre/
minute (L/min), typically 2 L/min to 8 L/min. nHF is commonly used for non-invasive respiratory support in preterm neonates. It may be
used in this population for primary respiratory support (avoiding, or prior to the use of mechanical ventilation via an endotracheal tube) for
prophylaxis or treatment of respiratory distress syndrome (RDS). This is an update of a review first published in 2011 and updated in 2016.
Objectives
To evaluate the benefits and harms of nHF for primary respiratory support in preterm infants compared to other forms of non-invasive
respiratory support.
Search methods
We used standard, extensive Cochrane search methods. The latest search date March 2022.
Selection criteria
We included randomised or quasi-randomised trials comparing nHF with other forms of non-invasive respiratory support for preterm
infants born less than 37 weeks' gestation with respiratory distress soon after birth.
Data collection and analysis

We used standard Cochrane Neonatal methods. Our primary outcomes were 1. death (before hospital discharge) or bronchopulmonary
dysplasia (BPD), 2. death (before hospital discharge), 3. BPD, 4. treatment failure within 72 hours of trial entry and 5. mechanical ventilation
via an endotracheal tube within 72 hours of trial entry. Our secondary outcomes were 6. respiratory support, 7. complications and 8.
neurosensory outcomes. We used GRADE to assess the certainty of evidence.
Main results
We included 13 studies (2540 infants) in this updated review. There are nine studies awaiting classification and 13 ongoing studies. The
included studies differed in the comparator treatment (continuous positive airway pressure (CPAP) or nasal intermittent positive pressure
ventilation (NIPPV)), the devices for delivering nHF and the gas flows used. Some studies allowed the use of 'rescue' CPAP in the event
of nHF treatment failure, prior to any mechanical ventilation, and some allowed surfactant administration via the INSURE (INtubation,
SURfactant, Extubation) technique without this being deemed treatment failure. The studies included very few extremely preterm infants
less than 28 weeks' gestation. Several studies had unclear or high risk of bias in one or more domains.
Nasal high flow therapy for primary respiratory support in preterm infants (Review) 1
Informed decisions.
Nasal high flow compared with continuous positive airway pressure for primary respiratory support in preterm infants
Eleven studies compared nHF with CPAP for primary respiratory support in preterm infants. When compared with CPAP, nHF may result in
little to no difference in the combined outcome of death or BPD (risk ratio (RR) 1.09, 95% confidence interval (CI) 0.74 to 1.60; risk difference
(RD) 0, 95% CI −0.02 to 0.02; 7 studies, 1830 infants; low-certainty evidence). Compared with CPAP, nHF may result in little to no difference
in the risk of death (RR 0.78, 95% CI 0.44 to 1.39; 9 studies, 2009 infants; low-certainty evidence), or BPD (RR 1.14, 95% CI 0.74 to 1.76; 8
studies, 1917 infants; low-certainty evidence). nHF likely results in an increase in treatment failure within 72 hours of trial entry (RR 1.70,
95% CI 1.41 to 2.06; RD 0.09, 95% CI 0.06 to 0.12; number needed to treat for an additional harmful outcome (NNTH) 11, 95% CI 8 to 17;
9 studies, 2042 infants; moderate-certainty evidence). However, nHF likely does not increase the rate of mechanical ventilation (RR 1.04,
95% CI 0.82 to 1.31; 9 studies, 2042 infants; moderate-certainty evidence). nHF likely results in a reduction in pneumothorax (RR 0.66, 95%
CI 0.40 to 1.08; 10 studies, 2094 infants; moderate-certainty evidence) and nasal trauma (RR 0.49, 95% CI 0.36 to 0.68; RD −0.06, 95% CI
−0.09 to −0.04; 7 studies, 1595 infants; moderate-certainty evidence).
Nasal high flow compared with nasal intermittent positive pressure ventilation for primary respiratory support in preterm infants
Four studies compared nHF with NIPPV for primary respiratory support in preterm infants. When compared with NIPPV, nHF may result in
little to no difference in the combined outcome of death or BPD, but the evidence is very uncertain (RR 0.64, 95% CI 0.30 to 1.37; RD −0.05,
95% CI −0.14 to 0.04; 2 studies, 182 infants; very low-certainty evidence). nHF may result in little to no difference in the risk of death (RR
0.78, 95% CI 0.36 to 1.69; RD −0.02, 95% CI −0.10 to 0.05; 3 studies, 254 infants; low-certainty evidence). nHF likely results in little to no
difference in the incidence of treatment failure within 72 hours of trial entry compared with NIPPV (RR 1.27, 95% CI 0.90 to 1.79; 4 studies,
343 infants; moderate-certainty evidence), or mechanical ventilation within 72 hours of trial entry (RR 0.91, 95% CI 0.62 to 1.33; 4 studies,
343 infants; moderate-certainty evidence). nHF likely results in a reduction in nasal trauma, compared with NIPPV (RR 0.21, 95% CI 0.09 to
0.47; RD −0.17, 95% CI −0.24 to −0.10; 3 studies, 272 infants; moderate-certainty evidence). nHF likely results in little to no difference in the
rate of pneumothorax (RR 0.78, 95% CI 0.40 to 1.53; 4 studies, 344 infants; moderate-certainty evidence).
Nasal high flow compared with ambient oxygen
We found no studies examining this comparison.
Nasal high flow compared with low flow nasal cannulae
We found no studies examining this comparison.
Authors' conclusions
The use of nHF for primary respiratory support in preterm infants of 28 weeks' gestation or greater may result in little to no difference in
death or BPD, compared with CPAP or NIPPV. nHF likely results in an increase in treatment failure within 72 hours of trial entry compared
with CPAP; however, it likely does not increase the rate of mechanical ventilation. Compared with CPAP, nHF use likely results in less
nasal trauma and likely a reduction in pneumothorax. As few extremely preterm infants less than 28 weeks' gestation were enrolled in the
included trials, evidence is lacking for the use of nHF for primary respiratory support in this population.
PLAIN LANGUAGE SUMMARY
Nasal high flow therapy for breathing support in preterm babies
Review question
In preterm babies, what are the benefits and harms of nasal high flow therapy (high flow) when used for breathing support soon after birth,
compared with other types of non-invasive breathing support?
What is respiratory support and how is it treated?
Preterm infants (born before their due date) often require support with their breathing soon after birth. Non-invasive respiratory support
is provided without placing a breathing tube in the baby's windpipe. There are several types of non-invasive respiratory support. High
flow is one type that delivers warm air and oxygen via two small prongs that sit inside the infant's nostrils. Alternatives to high flow
include continuous positive airway pressure (CPAP), where continuous pressure (rather than flow) of oxygen is given via larger prongs or
a mask, and nasal intermittent positive pressure ventilation (NIPPV) where, in addition to CPAP, inflations of oxygen at a higher pressure
are occasionally given.
What did we do?
We searched medical databases for well-designed studies evaluating the benefits and harms of high flow respiratory support in preterm
infants compared to other forms of non-invasive respiratory support.
What did we find?
Informed decisions.
We found 13 studies including 2540 preterm babies that compared high flow with other non-invasive ways of supporting babies' breathing
soon after birth. There are nine studies awaiting classification and 13 ongoing studies. The included studies differed in the treatments they
compared, the flows of oxygen used, whether CPAP could be used if high flow did not work and the approach to the use of surfactant (a
medication used to help prevent the small airways collapsing down) in babies with more severe breathing difficulties.
What did we find?
When used soon after birth in preterm babies, high flow may make little to no difference to death or bronchopulmonary dysplasia (a chronic
lung disease in preterm babies) compared with CPAP or NIPPV. High flow probably increases treatment failure compared with CPAP. For
example, babies treated with high flow might have needed higher oxygen concentrations or had worse blood test results. CPAP worked
better than high flow in around 10 more babies out of every 100. However, high flow probably makes little to no difference to the likelihood
of needing intubation (placement of a breathing tube). High flow probably caused less damage to the infant's nose, compared with CPAP
or NIPPV and probably reduced the risk of pneumothorax (air in the space between the lung and the chest wall). There were very few
extremely preterm infants (born before 28 weeks' gestation) included in these studies. Therefore, we remain unsure about the benefits and
harms of high flow soon after birth for extremely preterm infants.
What are the limitations of the evidence?
Overall, we have very low to moderate confidence in these findings. Our confidence is limited because clinicians in the studies knew which
treatment babies received; the results varied widely as some studies showed benefit with one type of breathing support while other studies
showed benefit with the comparator type of breathing support; and there were low numbers of events for some outcomes making it difficult
to compare groups.
How up to date is this evidence?
The search is up to date as of 12 March 2022.
SUMMARY OF FINDINGS
Summary of findings 1. Nasal high flow compared to continuous positive airway pressure for primary respiratory support in preterm infants
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Nasal high flow (nHF) compared to continuous positive airway pressure (CPAP) for primary respiratory support in preterm infants
Patient or population: preterm infants requiring primary respiratory support

Setting: neonatal intensive care units (Australia, China, Iran, Israel, Italy, Korea, Norway, Turkey, USA)
Intervention: nHF
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Comparison: CPAP
Outcomes Anticipated absolute effects* Relative effect № of partici- Certainty of Comments

(95% CI) (95% CI) pants the evidence
(studies) (GRADE)
Risk with CPAP Risk with nHF
Death (before hospital discharge) or 47 per 1000 52 per 1000 RR 1.09 1830 ⊕⊕⊝⊝ nHF may result in little to no
BPD (35 to 76) (0.74 to 1.60) (7 RCTs) Lowa,b difference in death or BPD.
(supplemental oxygen/respiratory sup-
port at 36 weeks' postmenstrual age if
born < 32 weeks' gestation, or 28 days if
born ≥ 32 weeks' gestation)
Death (before hospital discharge) 23 per 1000 18 per 1000 RR 0.78 2009 ⊕⊕⊝⊝ nHF may result in little to no
(10 to 31) (0.44 to 1.39) (9 RCTs) Lowa,b difference in death.
BPD (supplemental oxygen/respiratory 33 per 1000 37 per 1000 RR 1.14 1917 ⊕⊕⊝⊝ nHF may result in little to no
support at 36 weeks' postmenstrual age (24 to 58) (0.74 to 1.76) (8 RCTs) Lowa,b difference in BPD.
if born < 32 weeks' gestation, or 28 days if
born ≥ 32 weeks' gestation)
Treatment failure within 72 hours of tri- 131 per 1000 223 per 1000 RR 1.70 2042 ⊕⊕⊕⊝ nHF likely results in an in-
al entry (185 to 270) (1.41 to 2.06) (9 RCTs) Moderatec crease in treatment failure

within 72 hours of trial entry.
Mechanical ventilation within 72 hours 118 per 1000 122 per 1000 RR 1.04 2042 ⊕⊕⊕⊝ nHF likely does not increase
of trial entry (96 to 154) (0.82 to 1.31) (9 RCTs) Moderated mechanical ventilation within
72 hours of trial entry.
Pneumothorax (during assigned treat- 34 per 1000 22 per 1000 RR 0.66 2094 ⊕⊕⊕⊝ nHF likely results in a reduc-
ment) (14 to 37) (0.40 to 1.08) (10 RCTs) Moderatea,e tion in pneumothorax.
Nasal trauma (during assigned treat- 125 per 1000 61 per 1000 RR 0.49 1595 ⊕⊕⊕⊝ nHF likely results in a reduc-
ment) (45 to 85) (0.36 to 0.68) (7 RCTs) tion in nasal trauma.
4
Moderatef
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and
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its 95% CI).
BPD: bronchopulmonary dysplasia; CI: confidence interval; CPAP: continuous positive airway pressure; nHF: nasal high flow; RCT: randomised controlled trial; RR: risk ra-
tio.
GRADE Working Group grades of evidence

High certainty: we are very confident that the true effect lies close to that of the estimate of the effect.
Better health.
Informed decisions.
Trusted evidence.
Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is
substantially different.
Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.
Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
aBlinding of nHF and CPAP not possible, but objective outcome assessment therefore not downgraded.
bDowngraded two levels due to very serious concerns regarding imprecision: wide confidence intervals including clinically important benefit and harm.
cDowngraded one level due to serious concerns regarding risk of bias. Blinding of nHF and CPAP not possible. Most trials had objective criteria, but some included subjective
criteria or allowed the use of surfactant.
dDowngraded one level due to serious concerns regarding risk of bias. Blinding of nHF and CPAP not possible. Most trials had objective criteria, but some allowed cross-over to
CPAP with nHF failure, or bilevel positive airway pressure/nasal intermittent positive pressure ventilation with CPAP failure.
eDowngraded one level due to serious concerns regarding imprecision: fewer infants than optimal information size.
fDowngraded one level due to serious concerns regarding risk of bias: blinding of nHF and CPAP not possible, with risk of bias in outcome assessment.
Summary of findings 2. Nasal high flow compared to nasal intermittent positive pressure ventilation for primary respiratory support in preterm
infants
Nasal high flow (nHF) compared to nasal intermittent positive pressure ventilation (NIPPV) for primary respiratory support in preterm infants
Patient or population: preterm infants requiring primary respiratory support

Setting: neonatal intensive care units (China, Iran)
Intervention: nHF

Comparison: NIPPV
Outcomes Anticipated absolute effects* Relative effect № of partici- Certainty of Comments

(95% CI) (95% CI) pants the evidence
(studies) (GRADE)
Risk with NIP- Risk with nHF
PV
Death (before hospital discharge) or 144 per 1000 92 per 1000 RR 0.64 182 ⊕⊝⊝⊝ nHF may have little to no effect
BPD (supplemental oxygen/respirato- (43 to 198) (0.30 to 1.37) (2 RCTs) Very lowa,b on death or BPD but the evidence
ry support at 36 weeks' postmenstrual is very uncertain.
5
age if born < 32 weeks' gestation, or 28
days if born ≥ 32 weeks' gestation)
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Death (before hospital discharge) 102 per 1000 80 per 1000 RR 0.78 254 ⊕⊕⊝⊝ nHF may result in little to no dif-
(37 to 173) (0.36 to 1.69) (3 RCTs) Lowb,c ference in death.
BPD (supplemental oxygen/respirato- 118 per 1000 140 per 1000 RR 1.19 271 ⊕⊕⊝⊝ nHF may result in little to no dif-
ry support at 36 weeks' postmenstrual (78 to 249) (0.66 to 2.12) (3 RCTs) Lowb,c ference in BPD.
age if born < 32 weeks' gestation, or 28
days if born ≥ 32 weeks' gestation)
Better health.
Informed decisions.
Trusted evidence.
Treatment failure within 72 hours of 231 per 1000 210 per 1000 RR 1.27 343 ⊕⊕⊕⊝ nHF may result in little to no dif-
trial entry (143 to 308) (0.90 to 1.79) (4 RCTs) Moderated ference in treatment failure with-
in 72 hours of trial entry.
Mechanical ventilation within 72 199 per 1000 179 per 1000 RR 0.91 (0.62 to 343 ⊕⊕⊕⊝ nHF likely results in little to no
hours of trial entry (109 to 290) 1.33) (4 RCTs) Moderated difference in mechanical ventila-
tion within 72 hours of trial entry.
Pneumothorax (during assigned 98 per 1000 76 per 1000 RR 0.78 344 ⊕⊕⊕⊝ nHF likely results in little to no
treatment) (39 to 149) (0.40 to 1.53) (4 RCTs) Moderatec,e difference in pneumothorax.
Nasal trauma (during assigned treat- 212 per 1000 44 per 1000 RR 0.21 272 ⊕⊕⊕⊝ nHF likely results in a reduction
ment) (19 to 99) (0.09 to 0.47) (3 RCTs) Moderatea in nasal trauma.
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and
its 95% CI).
BPD: bronchopulmonary dysplasia; CI: confidence interval; nHF: nasal high flow; NIPPV: nasal intermittent positive pressure ventilation; RCT: randomised controlled trial;
RR: risk ratio.
GRADE Working Group grades of evidence

High certainty: we are very confident that the true effect lies close to that of the estimate of the effect.
Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is

substantially different.
Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.
Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
aDowngraded one level due to serious concerns regarding risk of bias: blinding of nHF and NIPPV not possible and unclear objectivity of outcome assessment.
bDowngraded two levels due to very serious concerns regarding imprecision: wide confidence intervals including clinically important benefit and harm.
cBlinding of nHF and NIPPV not possible, but objective outcome assessment therefore not downgraded.
dDowngraded one level due to serious concerns regarding risk of bias: blinding of nHF and NIPPV not possible. Most trials had objective criteria, but some included subjective
criteria or allowed the use of surfactant.
eDowngraded one level due to imprecision: fewer infants than optimal information size.
6
Informed decisions.
Informed decisions.
BACKGROUND overdistension and pneumothorax from unmeasured positive end

expiratory pressure (PEEP) (Hegde 2013; Jasin 2008).
Description of the condition
The cost-effectiveness of nHF compared with CPAP is unclear,
Many preterm infants require assistance with their breathing after and is influenced by the cost and lifespan of the devices, the
birth. Respiratory support in preterm infants aims to improve gas cost of consumables and the efficacy of the treatment, given the
exchange and minimise apnoea, while limiting short- and long- associated costs of mechanical ventilation or surfactant therapy in
term respiratory and neurodevelopmental complications. Use of the event of treatment failure (Fleeman 2016; Huang 2018).
mechanical ventilation via an endotracheal tube and supplemental
oxygen increase the risk of bronchopulmonary dysplasia (BPD) How the intervention might work
(Davidson 2017; Schmölzer 2013). Non-invasive respiratory support
(i.e. without the use of an endotracheal tube) is therefore Several physiological mechanisms may contribute to the efficacy
commonly employed as a first-line therapy for prophylaxis or of nHF: provision of continuous distending pressure (Collins
treatment of respiratory distress syndrome (RDS) in preterm 2013a; Wilkinson 2008), improved alveolar ventilation due to
neonates. Non-invasive respiratory support may take several forms nasopharyngeal dead space washout (Dysart 2009; Liew 2020;
including 'low flow' nasal cannulae, continuous positive airway Sivieri 2017), and reduction of airway resistance and therefore
pressure (CPAP), nasal intermittent positive pressure ventilation 'work of breathing' (Lavizzari 2014; Saslow 2006; Shetty 2016).
(NIPPV), and nasal high flow (nHF).
nHF generates some continuous distending pressure in the airways,
Description of the intervention which varies with infant weight, flow rate and leak. The pharyngeal
pressure generated by nHF is similar to that of nasal CPAP and
Until recently, nasal CPAP has been the most common mode of increases with increased flow (Kubicka 2008; Lampland 2009;
non-invasive respiratory support in preterm neonates. Nasal CPAP Spence 2007; Wilkinson 2008). For a given flow, the delivered
provides continuous distending pressure via binasal prongs or a pressure appears to be inversely proportional to infant weight
nasal mask. It is an effective alternative to elective endotracheal (Kubicka 2008; Liew 2020; Wilkinson 2008).
intubation in very preterm infants for the treatment of RDS
(Morley 2008), and may reduce the risk of BPD (Schmölzer 2013). nHF use may provide washout of the nasopharyngeal dead space
Alternatives to CPAP include nasal intermittent positive pressure and subsequent carbon dioxide removal (Dysart 2009). Paediatric
ventilation (NIPPV) and nHF. NIPPV augments CPAP by providing (Bressan 2013), animal (Frizzola 2011), and bench top (Sivieri
inflations to a set peak pressure; these may be synchronised or non- 2017), studies have demonstrated lower carbon dioxide levels in
synchronised with the infant's own breathing efforts (Lemyre 2017). blood with the use of nHF, and one study in preterm neonates
also demonstrated flow-related reductions in nasopharyngeal end-
nHF delivers heated, humidified air or oxygen, or both, via small expiratory carbon dioxide levels (Liew 2020).
tapered binasal prongs, at gas flows of more than 1 litre/minute
(L/min). In contrast to the tightly fitting prongs of nasal CPAP, The large surface area of the nasopharynx, whilst allowing heating
nHF prongs are designed to avoid occlusion of the nares; leak and humidification of inspired gas, causes resistance to inspiratory
around the prongs serves to avoid excessive pressure generation. flow. nHF delivers gas flows above the peak inspiratory flow of the
Gas flow, rather than pressure, is set by the clinician, and neonatal patient, which reduces resistance and work of breathing (Dysart
gas flows are generally 2 L/min to 8 L/min. nHF is an alternative 2009).
form of non-invasive respiratory support for preterm infants with
RDS. Compared with CPAP, nHF may be preferred by nursing staff The efficacy of non-invasive respiratory support (CPAP or nHF) in
(Roberts 2014), and parents (Klingenberg 2014), due to ease of use avoiding intubation and mechanical ventilation may be influenced
and comfort of the infant (Osman 2015). by the approach to treatment with exogenous surfactant.
Surfactant therapy improves respiratory mechanics in preterm
Both CPAP and nHF systems may have adverse effects in newborns. infants with RDS (Bahadue 2012). Surfactant may be administered
CPAP interfaces may be bulky and skilled nursing care is required to infants receiving CPAP or nHF via brief placement of an
to optimally manage infants, and CPAP use is associated with endotracheal tube using the INSURE (INtubation, SURfactant,
nasal trauma (Imbulana 2018), and air leaks from the lung Extubation) procedure (Herting 2013), or via a thin catheter briefly
(pneumothorax) (Ho 2020). inserted into the trachea (Abdel-Latif 2021).
Risk factors for severe nasal trauma in preterm infants include Why it is important to do this review
lower gestational age, lower birth weight, and incorrect sizing
There is currently very little evidence regarding nHF use in
and positioning of CPAP prongs (Imbulana 2018). nHF may be
extremely preterm infants. With increasing use of nHF, evidence
associated with a lower risk of nasal trauma, compared with CPAP
regarding comparative efficacy of the therapy in different
(Imbulana 2018).
gestational age (GA) groups may be of importance to clinicians.
Pneumothorax is another recognised complication of CPAP and
The purpose of this review was to compare the efficacy and harms
nHF; the reported incidence of this complication in preterm infants
of nHF with other methods of first-line non-invasive respiratory
with RDS is variable (Dunn 2011; Morley 2008). Pneumothoraces
support in preterm infants.
occur predominantly in surfactant-deplete preterm infants
receiving treatment for RDS, rather than after surfactant treatment
or a period of mechanical ventilation, and are likely secondary
to overdistension of some areas of the lung. There were early
concerns that the use of nHF may lead to an increase in lung
Informed decisions.
OBJECTIVES disease' or 'CLD' without a clear accompanying definition were

still included in this outcome.
To evaluate the benefits and harms of nHF for primary respiratory • Treatment failure (as defined in the included studies) within 72
support in preterm infants compared to other forms of non-invasive hours of trial entrya.
respiratory support.
• Mechanical ventilation via an endotracheal tube within 72 hours
METHODS of trial entrya.
Criteria for considering studies for this review Note: a see Types of outcome measures.
Types of studies Secondary outcomes

We included all randomised controlled trials (RCTs) and quasi- Respiratory support
randomised studies, including cross-over studies and cluster-
• Mechanical ventilation via an endotracheal tube at any time
randomised trials. Trials with a superiority, non-inferiority or point following trial entry.
equivalence hypothesis were included. We included studies
reported in abstract form in the Characteristics of studies awaiting • Duration of mechanical ventilation via an endotracheal tube
classification table. For studies with only a subset of relevant (days, or PMA at cessation).
participants, we contacted study authors to obtain data. • Duration of any form of respiratory support (mechanical
ventilation, CPAP, NIPPV, nHF or supplemental oxygen) (days, or
Types of participants PMA at cessation).
We included preterm infants (born less than 37 weeks' gestation) • Surfactant administration (via any method).
receiving non-invasive respiratory support soon after birth, either • Duration of hospitalisation (days, or PMA at hospital discharge).
prophylactically or for treatment of RDS without a prior period of
Complications
mechanical ventilation via an endotracheal tube.
• Air leak syndromes (pneumothorax, pneumomediastinum,
The previous versions of this review also included the use of nHF pneumopericardium or pulmonary interstitial emphysema
for other indications in preterm infants (Wilkinson 2011; Wilkinson (PIE)) reported either individually or as a composite outcome
2016). Due to the increase in number of studies of nHF in preterm (during assigned treatment).
infants, we limited this update to studies of nHF as primary
• Nasal trauma (defined as erythema or erosion of the nasal
respiratory support (see Differences between protocol and review).
mucosa, nares or septum). Note some studies reported nasal
The efficacy of nHF for postsurfactant or postextubation respiratory
trauma severity as a continuous outcome and could not be
support will be assessed in a separate Cochrane Review.
included in meta-analysis (during assigned treatment).
Types of interventions • Nosocomial sepsis (defined as positive blood or cerebrospinal
fluid (CSF) cultures taken after five days of age). Note: some
For the purposes of this review, we defined nHF as the delivery of studies used alternate definitions, or did not define sepsis: such
oxygen or blended oxygen and air via nasal cannulae at gas flows data were included in the meta-analysis.
of greater than 1 L/min.
• Gastrointestinal perforation or severe necrotising enterocolitis
Comparator interventions included: (NEC) (stage II or more according to Bell's criteria (Bell 1978)).
Note: some included studies only reported the incidence of NEC,
• nHF compared with CPAP; and were included in the analysis of this outcome.
• nHF compared with NIPPV; • Days to attain full feedsa.
• nHF compared with ambient oxygen;
Neurosensory outcomes
• nHF compared with low flow nasal cannulae.
• Retinopathy of prematurity (ROP): any stage, and stage 3 or
Types of outcome measures greater.
Outcome measures that were not in the previous versions of the • Long-term neurodevelopment (rates of cerebral palsy on
review(s) (Wilkinson 2011; Wilkinson 2016; see Differences between physician assessment; developmental delay, i.e. intelligence
protocol and review), or that were modified or included after review quotient 2 standard deviations (SD) less than the mean
of the available data, are marked with an 'a'. We did not exclude on validated assessment tools such as Bayley's Mental
studies based on the non-reporting of outcomes of interest. Developmental Index), blindness, hearing impairment requiring
amplification.
Primary outcomes
Note: a see Types of outcome measures.
• Death (before hospital discharge) or BPD (as defined below).
• Death (before hospital discharge). Search methods for identification of studies
• BPD, defined as receiving supplemental oxygen or respiratory For this update, we developed new search strategies to increase
support (or both) at 36 weeks' postmenstrual age (PMA) for sensitivity.
infants born at less than 32 weeks' gestation, or at 28 days of
age for infants born at 32 weeks' gestation or greater. Note: data
from studies that reported an outcome of 'BPD', 'chronic lung
Informed decisions.
Electronic searches The Cochrane Neonatal Group acknowledges that Embase is a

recommended source and will be searched for subsequent updates
The Cochrane Neonatal Group Information Specialist, M Fiander,
of this review.
wrote the search strategies in consultation with the review authors.
Search strategies are available in Appendix 1. Searching other resources
We searched the following databases without date, language or We searched the reference lists of any articles selected for inclusion
publication type limits: in this review in order to identify additional relevant articles.
• Cochrane Central Register of Controlled Trials via CRS (2022, Data collection and analysis
Issue 3);
We used the standard methods of Cochrane Neonatal.
• Ovid MEDLINE(R) and Epub Ahead of Print, In-Process, In-Data-
Review & Other Non-Indexed Citations, Daily and Versions (1946 Selection of studies
to 10 March 2022);
We included all RCTs and quasi-randomised trials fulfilling the
• CINAHL via EBSCO (1981 to 12 March 2022).
selection criteria. The review authors (KH, DW, AGDP, BJM) reviewed
We searched the following clinical trial registries for ongoing or the results of the search and independently selected the studies
completed trials: for inclusion. The review authors resolved any disagreement by
discussion. Search results were managed using Endnote and
• World Health Organization's International Clinical Trials Registry Covidence software. Selection was recorded in sufficient detail to
Platform (ICTRP) (www.who.int/ictrp/search/en/); complete the PRISMA flow diagram (Figure 1).
• ISRCTN Registry (www.isrctn.com).
Informed decisions.
Figure 1. Study flow diagram.
801 records 17 records

identified through identified in trial
database searching registries
203 duplicates
removed
598 references; 17 543 references; 4

trial registry trial registry
records screened records excluded
55 full-text articles;
33 full-text articles
13 trial registration
excluded
records assessed
13 studies included
(3 from the original
review; 10 new
studies); 9 studies
awaiting
assessment; 13
ongoing studies
13 studies included
in quantitative
synthesis
(meta-analysis)
Informed decisions.
Data extraction and management method described by Wan 2014, as recommended by the Cochrane
Handbook for Systematic Reviews of Interventions (Higgins 2020),
Two review authors (KH and BJM) independently performed
acknowledging that it was not possible to ascertain whether these
trial searches, all review authors performed assessments of
outcomes were normally distributed.
methodology and extraction of data, and compared and resolved
any differences found at each stage. For each trial, we collected Assessment of heterogeneity
information regarding blinding of randomisation, the intervention
and outcome measurements as well as completeness of follow- We described the clinical diversity and methodological variability
up. For any cross-over trials, only data from the first period were of the evidence in the review text and study tables describing
to be included. Where any queries arose or where additional data study characteristics including design features, population
were required, we made attempts to contact study authors for characteristics and intervention details. To assess statistical
clarification. For trials in which a review author (i.e. BJM) was an heterogeneity, we visually inspected forest plots and described
investigator, other review authors performed assessments about the direction and magnitude of effects and the degree of overlap
eligibility and data extraction for those trials. between CIs. We also considered the statistics generated in forest
plots that measured statistical heterogeneity. We used the I2
Assessment of risk of bias in included studies statistic to quantify inconsistency amongst the trials in each
analysis. We considered the P value from the Chi2 test to assess
Two review authors (KH and BJM) independently assessed the
if this heterogeneity was significant (P < 0.1). If we identified
risk of bias (low, high or unclear) of all included trials using the
substantial heterogeneity, we planned to report the finding and
Cochrane RoB 1 tool (Higgins 2011), for the following domains:
explore possible explanatory factors using prespecified subgroup
• sequence generation (selection bias); analysis. Our interpretation of the I2 statistic took into account an
understanding that measures of heterogeneity will be estimated
• allocation concealment (selection bias);
with high uncertainty when the number of studies is small as
• blinding of participants and personnel (performance bias); recommended by the Cochrane Handbook for Systematic Reviews of
• blinding of outcome assessment (detection bias); Interventions (Higgins 2020).
• incomplete outcome data (attrition bias);
Assessment of reporting biases
• selective reporting (reporting bias);
• any other bias. We assessed reporting bias by comparing the stated primary
and secondary outcomes and reported outcomes. Where study
For trials in which a review author (i.e. BJM) was an investigator, KH protocols were available, we compared these to the full
and AGDP or DW performed risk of bias assessment for those trials. publications to determine the likelihood of reporting bias.
We resolved any disagreements by discussion or by a third assessor.
See Appendix 2 for a more detailed description of risk of bias for Data synthesis
each domain. We performed meta-analysis using Review Manager Web (RevMan
Measures of treatment effect Web 2020). For categorical outcomes, we calculated the estimates
of RR and RD, each with its 95% CI; for continuous outcomes, we
We extracted categorical data (e.g. number of deaths or with BPD) calculated the MD or SMD, each with its 95% CI. We used a fixed-
for each intervention group, and calculated risk ratio (RR), risk effect model to combine data where it was reasonable to assume
difference (RD) and number needed to treat for an additional that studies were estimating the same underlying treatment effect.
beneficial outcome (NNTB), or number needed to treat for an Where there was evidence of clinical heterogeneity, we attempted
additional harmful outcome (NNTH) as appropriate. We obtained to explain this based on the different study characteristics and
means and SDs for continuous data (e.g. duration of respiratory subgroup analyses. If meta-analysis was not possible, we presented
support, or duration of supplemental oxygen) and calculated individual trial data separately.
mean differences (MD) (where studies used the same scale) or
standardised mean difference (SMD) (where studies used different Subgroup analysis and investigation of heterogeneity
scales). We calculated 95% confidence interval (CI) for each We prespecified subgroup analyses for primary outcomes to
measure of effect. compare effects by gestation at birth when data were available:
Unit of analysis issues
• less than 28 weeks' gestation versus 28 to 32 weeks' gestation
The unit of analysis was the participating infant as all trials versus 32 weeks' gestation or greater.
randomised infants individually, and an infant was considered only
once in the analysis. We planned to explore moderate or high levels of heterogeneity (I2
> 50%) in these subgroup analyses of primary outcomes:
Dealing with missing data
• surfactant administration permitted during the intervention
Where feasible, we carried out analysis on an intention-to- period (without this being deemed treatment failure) versus not
treat basis for all outcomes. We requested additional data from permitted;
study authors where important outcome data were missing, or • second-line CPAP permitted in the nHF arm prior to mechanical
presented without the GA subgroups of interest (see Subgroup ventilation versus not permitted.
analysis and investigation of heterogeneity). When studies reported
only medians for continuous data, and authors were unable to See: Differences between protocol and review.
provide means and SDs, we calculated the means using the
Informed decisions.
Sensitivity analysis Results of the search

We planned to perform sensitivity analyses if: Database searches identified 801 references. After removing
203 duplicates, 598 references were available for title/abstract
• there was unexplained high heterogeneity (I2 > 75%) (explored screening. We excluded 543 records during title/abstract screening
by removing the outlying trial or trials); and reviewed 55 full-text articles. We excluded 33 full-text
• a trial with high risk of bias (including high level of missing reports with reasons (Excluded studies; Characteristics of excluded
outcome data) was included in the meta-analysis of an outcome studies table); placed nine potentially relevant studies in awaiting
where the other studies had low risk of bias (removed the study classification (Characteristics of studies awaiting classification
with high risk of bias). table); and included 13 studies (Included studies; Characteristics
of included studies table) in our analysis. One included study was
Summary of findings and assessment of the certainty of the published only in abstract form, but we obtained data from the
evidence authors and were thus able to include it in this review (Nair 2005).
We used the GRADE approach, as outlined in the GRADE Handbook Trial registry searches identified 17 records; of these 13 appear
to assess the certainty of evidence of the following clinically relevant and are ongoing (Characteristics of ongoing studies table;
relevant outcomes (Schünemann 2013): Ongoing studies).
• death or BPD; See Figure 1 for details of study selection process.

• death; Several RCTs of nHF compared with other means of non-
• BPD; invasive support are currently in progress, have been
• treatment failure within 72 hours of trial entry; completed but are not yet published or are awaiting further
• mechanical ventilation within 72 hours of trial entry; assessment. Nine studies awaiting classification (Awad 2021;
Balasubramanian 2022; Cetinkaya 2018; Febre 2015; Iskandar
• pneumothorax;
2019; Lawrence 2012; Oktem 2021; Park 2011; Shirvani 2019) and
• nasal trauma. 13 are ongoing (ACTRN12610000677000; ACTRN12611000233921;
Two review authors (KH and BJM) independently assessed the CTRI/2017/09/009910; CTRI/2019/10/021633; Irct2016052510026N;
certainty of the evidence for each of the outcomes above. The Irct20180226038865N; Irct20190623043988N;
trials in which BJM was an investigator were assessed by KH Irct20200616047788N; ISRCTN66716753; NCT01270581;
and DW. We considered evidence from RCTs as high certainty but NCT02055339; NCT02499744; UMIN000018983). See Characteristics
downgraded the evidence one level for serious (or two levels for of studies awaiting classification and Characteristics of ongoing
very serious) limitations based upon the following: design (risk studies tables for further details.
of bias), consistency across studies, directness of the evidence, Included studies
precision of estimates, and presence of publication bias. We used
GRADEpro GDT to create two summary of findings tables to report We included 13 studies (2540 preterm infants) in our review (see
the certainty of the evidence (GRADEpro GDT). The summary of Characteristics of included studies table).
findings tables were for two comparisons: nHF compared to CPAP
for primary respiratory support in preterm infants (Summary of Of those 13 included studies:
findings 1) and nHF compared to NIPPV for primary respiratory
• 11 were available as full journal publications (Armanian 2019;
support in preterm infants (Summary of findings 2).
Demirel 2019; Farhat 2018; Kugelman 2015; Lavizzari 2016;
The GRADE approach results in an assessment of the certainty of a Manley 2019; Murki 2018; Roberts 2016; Sharma 2019; Shin 2017;
body of evidence as one of four grades. Yoder 2013);
• one was published as an abstract (Nair 2005), but study authors
• High certainty: we are very confident that the true effect lies provided additional unpublished data enabling its inclusion in
close to that of the estimate of the effect. this review;
• Moderate certainty: we are moderately confident in the effect • Wang 2018 was published in English in abstract form, and in full-
estimate; the true effect is likely to be close to the estimate of the text in Chinese;
effect, but there is a possibility that it is substantially different. • seven study authors kindly provided additional data (Kugelman
• Low certainty: our confidence in the effect estimate is limited; 2015; Lavizzari 2016; Manley 2019; Murki 2018; Nair 2005;
the true effect may be substantially different from the estimate Roberts 2016; Yoder 2013);
of the effect. • overall, trials enrolled participants from 26 to 36 weeks'
• Very low certainty: we have very little confidence in the effect gestation (very few infants less than 28 weeks' gestation
estimate; the true effect is likely to be substantially different included in any study): nHF flows ranged from 2.5 L/min to 8
from the estimate of effect. L/min, CPAP pressures ranged from 4 cmH2O to 8 cmH2O and
NIPPV settings varied (peak inspiratory pressure (PIP) 14 cmH2O
RESULTS
to 22 cmH2O, PEEP 5 cmH2O to 6 cmH2O);
Description of studies • nine included studies compared nHF with CPAP for primary
respiratory support in preterm infants; two compared nHF with
We have provided results of the search for this review update in the
NIPPV; and two studies compared nHF with both CPAP and
study flow diagram (Figure 1).
NIPPV;
Informed decisions.
• no studies compared nHF with ambient oxygen or low flow nasal • Manley 2019 was a multicentre non-inferiority study in non-
cannulae; tertiary special care nurseries in Australia that enrolled 754 term
• where stated, studies were funded internally or by government and preterm infants. Of these, 379 infants were preterm and
organisations; some studies had nHF equipment provided by were included in this review. The study was undertaken from 13
manufacturers. April 2015 to 28 November 2017. Infants were less than 24 hours
of age, GA 31 weeks or greater and birth weight greater than 1200
Comparison 1. Nasal high flow compared with continuous g with respiratory distress requiring non-invasive respiratory
positive airway pressure for primary respiratory support in support or supplemental oxygen. Infants were randomised to
preterm infants (11 studies) nHF (185 preterm infants; initial gas flow 6 L/min, maximum 8
L/min) or CPAP (194 preterm infants; initial pressure 6 cmH2O,
• Armanian 2019 was a multicentre study in Iran that enrolled
109 preterm neonates with birth weight less than 1500 g (mean maximum 8 cmH2O). The primary outcome was treatment
GA 30 weeks) and RDS based on clinical examination and chest failure, defined by prespecified criteria. Infants in the nHF
X-ray findings. The study was undertaken from February 2015 group who reached treatment failure criteria could receive CPAP
to March 2016. Infants were randomised to nHF (35 infants; with the aim of avoiding mechanical ventilation. Surfactant
2.5 L/min for infants less than 1000 g, 3 L/min for infants 1000 was only administered following endotracheal intubation and
g to 1500 g), nasal CPAP (37 infants; pressure 5 cmH2O to 6 mechanical ventilation.
cmH2O) or NIPPV (37 infants; PIP 16 cmH2O to 20 cmH2O, • Murki 2018 was a multicentre non-inferiority study in India that
PEEP 5 cmH2O to 6 cmH2O, rate 50/min, inspiratory time enrolled 272 preterm infants 28 to 36 weeks' gestation with
respiratory distress. The study was undertaken from 9 October
0.4 seconds). The primary outcomes were treatment failure
2015 to 26 November 2016. Infants were randomised to nHF
(defined by prespecified criteria) and duration of RDS treatment
(133 infants; initial flow 5 L/min, maximum 7 L/min) or CPAP
(not defined). Surfactant could be administered by the INSURE
(139 infants; initial pressure 5 cmH2O, maximum 7 cmH2O). The
technique without this being deemed treatment failure.
primary outcome was treatment failure, defined by prespecified
• Demirel 2019 was a single-centre study in Turkey that enrolled
criteria. Infants in the nHF group who reached treatment failure
107 preterm infants of 32 weeks' gestation or less who did not
criteria could receive CPAP with the aim of avoiding mechanical
require intubation, with or without respiratory distress. The
ventilation. Surfactant could be administered by the INSURE
study was undertaken from February 2017 to February 2018.
technique without this being deemed treatment failure.
Infants were randomised to nHF (53 infants; initial flow 6 L/
min, maximum 8 L/min) or CPAP (54 infants; initial pressure • Nair 2005 was a single-centre study in the USA, published in
6 cmH2O, maximum 7 cmH2O). The primary outcome was abstract form, that enrolled 67 preterm infants of 27 to 34
weeks' gestation with respiratory distress in the first six hours
treatment failure, based on prespecified criteria. Surfactant
after birth. Infants were randomised to nHF (33 infants; initial
could be administered by the INSURE technique without this
flow 5 L/min to 6 L/min, maximum not stated) or CPAP (34
being deemed treatment failure.
infants; initial pressure 5 cmH2O to 6 cmH2O, maximum not
• Farhat 2018 was a single-centre study in Iran that enrolled
stated). The primary outcome was respiratory failure requiring
160 preterm infants 28 to 34 weeks' gestation with respiratory
endotracheal intubation, based on prespecified criteria. After
distress. The study was undertaken from April 2014 to November
randomisation, surfactant was only administered following
2014. Infants were randomised to nHF (54 infants; weight-based,
endotracheal intubation and mechanical ventilation.
initial flow rate 2 L/min or greater, maximum 5 L/min), CPAP
(53 infants; initial pressure 6 cmH2O, maximum 8 cmH2O) or • Roberts 2016 was a multicentre non-inferiority study in Australia
and Norway that enrolled 564 preterm infants 28 to 36 weeks'
NIPPV (53 infants; initial PIP less than 18 cmH2O, maximum
gestation with respiratory distress. The study was undertaken
PIP 19 cmH2O, initial PEEP 4 cmH2O to 5 cmH2O, maximum from 27 May 2013 to 16 June 2015. Infants were randomised to
PEEP 6 cmH2O, rate and inspiratory time not stated). The nHF (289 infants; initial gas flow 6 L/min to 8 L/min, maximum
primary outcomes were need for endotracheal intubation and 8 L/min) or CPAP (294 infants; initial pressure 6 cmH2O to
mechanical ventilation within 72 hours, based on prespecified 8 cmH2O, maximum 8 cmH2O). The primary outcome was
criteria. Surfactant could be administered by the INSURE treatment failure within 72 hours of randomisation, defined
technique without this being deemed treatment failure. by prespecified criteria. Infants in the nHF group who reached
• Lavizzari 2016 was a single-centre non-inferiority study in Italy treatment failure criteria could receive second-line CPAP
that enrolled 316 preterm infants 29 to 36 weeks' gestation with with the aim of avoiding mechanical ventilation. Surfactant
mild–moderate respiratory distress. The study was undertaken was only administered following endotracheal intubation and
from 5 January 2012 to 28 June 2014. Infants were randomised mechanical ventilation.
to nHF (158 infants; initial flow 4 L/min to 6 L/min, maximum • Sharma 2019 was a single-centre study in India that enrolled
6 L/min) or nasal CPAP (158 infants; initial pressure 4 cmH2O 100 infants 26 to 34+6 weeks' gestation with mild–moderate
to 6 cmH2O, maximum 6 cmH2O). The primary outcome was respiratory distress within six hours of birth. Infants were
need for mechanical ventilation within 72 hours of commencing randomised to nHF (50 infants) or CPAP (50 infants). There was
respiratory support, based on prespecified criteria. The use no information regarding set flow rate or pressure. The primary
of bilevel positive airway pressure (BiPAP) was permitted in outcomes were duration of non-invasive support, duration of
the CPAP arm without this being deemed treatment failure. oxygen supplementation and treatment failure (no prespecified
Surfactant was administered via the INSURE technique if the criteria). The approach to surfactant treatment was not stated.
fraction of inspired oxygen (FiO2) increased to greater than 0.35, • Shin 2017 was a single-centre non-inferiority study in Korea that
without this being deemed treatment failure. enrolled 87 preterm infants 30 to 35 weeks' gestation less than
Informed decisions.
24 hours old with respiratory distress. The study was undertaken treatment failure defined by prespecified criteria. Following
from August 2010 to August 2013. Infants were randomised randomisation, surfactant was only administered following
to nHF (42 infants; initial flow rate 5 L/min, maximum 7 L/ endotracheal intubation and mechanical ventilation.
min) or CPAP (43 infants; initial pressure 5 cmH2O, maximum 7 • Wang 2018 was a single-centre study in China that enrolled
cmH2O). The primary outcome was the incidence of treatment 89 preterm infants 28 to 32 weeks' gestation and birth weight
failure (intubation and mechanical ventilation, time frame not 1000 g to 1500 g with respiratory distress. Infants were
defined), based on prespecified criteria. After treatment failure randomised to nHF (43 infants; initial flow 5 L/min, maximum
criteria were met, infants in the nHF group could receive 8 L/min) or NIPPV (46 infants; initial PIP 18 cmH2O, initial
CPAP, and infants in the CPAP group could receive BiPAP, PEEP 6 cmH2O, maximum not stated). The primary outcome
with the aim of avoiding mechanical ventilation. Surfactant was need for intubation and mechanical ventilation within 72
was only administered following endotracheal intubation and hours after birth, based on prespecified criteria. Surfactant
mechanical ventilation. was only administered following endotracheal intubation and
• Yoder 2013 was a multicentre study in the USA and China mechanical ventilation.
that enrolled 432 term and preterm infants of more than 28
weeks' gestation at birth who were planned to receive non- Comparison 3. Nasal high flow compared with ambient oxygen
invasive respiratory support either as primary support after No studies compared nHF with ambient oxygen.
birth or postextubation. Of all infants enrolled, 351 infants were
preterm, with 125 preterm infants in the primary support arm Comparison 4. Nasal high flow compared with low flow nasal
that were included in this review. The study was undertaken cannulae
from December 2007 to April 2012. Infants were randomised
to nHF (58 preterm infants; initial flow 3 L/min to 5 L/min, No studies compared nHF with low flow nasal cannulae.
maximum 6 L/min to 8 L/min) or CPAP (67 preterm infants; Excluded studies
initial pressure 5 cmH2O to 6 cmH2O, maximum 8 cmH2O). The
primary outcome was need for intubation within 72 hours of We excluded 12 new studies in this update.
commencing the allocated treatment, based on prespecified
In total we excluded 33 studies for the reasons described in the
criteria. After randomisation, surfactant was only administered
Characteristics of excluded studies table.
following endotracheal intubation and mechanical ventilation.
Studies awaiting classification
Comparison 2. Nasal high flow compared with nasal
intermittent positive pressure ventilation for primary There are nine studies awaiting classification (Awad 2021;
respiratory support in preterm infants (four studies) Balasubramanian 2022; Cetinkaya 2018; Febre 2015; Iskandar
2019; Lawrence 2012; Oktem 2021; Park 2011; Shirvani 2019). See
• Armanian 2019 was a multicentre study in Iran that enrolled 109
Characteristics of studies awaiting classification table for further
preterm neonates (mean GA 30 weeks) with respiratory distress
details.
to nHF, CPAP or NIPPV (see details under Comparison 1).
• Farhat 2018 was a single-centre study in Iran that enrolled Ongoing studies
160 preterm infants 28 to 34 weeks' gestation with respiratory
distress to nHF, CPAP or NIPPV (see details under Comparison 1). There are 13 are ongoing studies (ACTRN12610000677000;
ACTRN12611000233921; CTRI/2017/09/009910;
• Kugelman 2015 was a single-centre study in Iran that enrolled
CTRI/2019/10/021633; Irct2016052510026N; Irct20180226038865N;
76 preterm infants born less than 35 weeks' gestation, with
Irct20190623043988N; Irct20200616047788N; ISRCTN66716753;
birth weight greater than 1000 g, who required non-invasive
NCT01270581; NCT02055339; NCT02499744; UMIN000018983). See
respiratory support. Infants were treated with either nHF (38
Characteristics of ongoing studies table for further details.
infants; initial flow 1 L/min, maximum 5 L/min) or synchronised
NIPPV (38 infants; PIP 14 cmH2O to 22 cmH2O, PEEP 6 Risk of bias in included studies
cmH2O, rate 12/min to 30/min). The primary outcome was
See Figure 2; Figure 3.
Informed decisions.
Figure 2. Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Blinding of outcome assessment (detection bias): Mechanical ventilation within 72 hours of trial entry
Blinding of outcome assessment (detection bias): Nasal trauma
Blinding of participants and personnel (performance bias)
Incomplete outcome data (attrition bias): All outcomes

Random sequence generation (selection bias)
Allocation concealment (selection bias)
Selective reporting (reporting bias)

Other bias
Armanian 2019 + ? ? ? + − +
Demirel 2019 + + ? ? ? ? +
Farhat 2018 ? − ? ? − ? ? +
Kugelman 2015 ? + ? ? − + + +
Lavizzari 2016 + + ? ? + ? ?
Manley 2019 + + ? ? ? + + +
Murki 2018 + + ? ? ? + ? +
Nair 2005 ? + ? ? − ? ? +
Roberts 2016 + + ? ? ? + + +
Sharma 2019 + − ? − − − − +
Informed decisions.
Figure 2. (Continued)
Roberts 2016 ? ? ?
Sharma 2019 + − ? − − − − +
Shin 2017 + + ? ? − + ? +
Wang 2018 − − ? ? − + − +
Yoder 2013 + + ? ? − + ? +
Figure 3. Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages
across all included studies.
Random sequence generation (selection bias)

Allocation concealment (selection bias)
Blinding of participants and personnel (performance bias)
Blinding of outcome assessment (detection bias): Mechanical ventilation within 72 hours of trial entry
Blinding of outcome assessment (detection bias): Nasal trauma
Incomplete outcome data (attrition bias): All outcomes
Selective reporting (reporting bias)
Other bias
0% 25% 50% 75% 100%
Low risk of bias Unclear risk of bias High risk of bias
Allocation Four trials permitted the use of CPAP in infants who met
nHF treatment failure criteria, after the primary outcome was
Six studies described appropriate random sequence generation
determined, prior to endotracheal intubation and mechanical
and allocation concealment (Demirel 2019; Lavizzari 2016; Manley
ventilation (Manley 2019; Murki 2018; Roberts 2016; Shin 2017). In
2019; Murki 2018; Roberts 2016; Shin 2017). Armanian 2019
these four studies, a number of infants in the nHF group meeting
and Sharma 2019 reported incomplete information regarding
treatment failure criteria did not subsequently require mechanical
the process of allocation concealment. Farhat 2018 described a
ventilation. Two studies permitted the use of BiPAP in infants
'randomised convenience sampling method' that matched infants
who met CPAP failure criteria prior to endotracheal intubation and
on birth weight and GA, which indicates a potential for selection
mechanical ventilation (Lavizzari 2016; Shin 2017). Five studies
bias due to lack of both random sequence generation and
permitted the administration of surfactant via INSURE prior to
allocation concealment. Kugelman 2015 and Wang 2018 did not
meeting treatment failure criteria, in both infants receiving nHF and
fully describe the methods of random sequence generation.
CPAP or NIPPV (Armanian 2019; Demirel 2019; Farhat 2018; Lavizzari
Blinding 2016; Murki 2018). While all trials had objective failure criteria which
were to be met prior to switching to CPAP or BiPAP, or administering
Blinding of treatment allocation was not attempted in any study surfactant, there may still be potential for bias between groups due
except Sharma 2019, where authors stated the study was double- to clinician preference.
blinded, but gave no information regarding the process of blinding.
Due to the nature of the intervention, blinding was unlikely in these Incomplete outcome data
studies.
Three studies did not report the number of eligible infants,
There were prespecified criteria for treatment failure and the number who received the allocated intervention or whether
intubation in all studies except Sharma 2019. However, in several the analysis was performed using an intention-to-treat principle
studies, some criteria were potentially open to bias (e.g. duration (Demirel 2019; Farhat 2018; Wang 2018). Wang 2018 excluded
of FiO2 increase, frequency of blood gas analysis, and recording an unknown number of infants who were discharged prior to
completing the allocated intervention. Shin 2017 excluded one
of apnoea frequency and severity). Lack of blinding was also
infant from each arm of the trial prior to analysis. Sharma 2019 did
a potential source of bias for subjective outcomes such as the
not perform an intention-to-treat analysis; infants who underwent
presence of nasal mucosal injury.
mechanical ventilation were excluded from outcome reporting.
In Kugelman 2015, alterations to flow or the level of non-invasive
Selective reporting
support were at the discretion of treating clinicians, rather than
based on objective criteria. Four studies did not state which criteria Trial registration was not evident, or occurred after trial completion
they used for escalating non-invasive support (Armanian 2019; for seven studies, indicating the potential for selective reporting
Farhat 2018; Nair 2005; Sharma 2019). of outcomes (Demirel 2019; Farhat 2018; Lavizzari 2016; Nair 2005;
Sharma 2019; Shin 2017; Wang 2018). The trial registration by
Informed decisions.
Armanian 2019 only included two of the three intervention arms Certainty of evidence (GRADE)
present in the published study. Sharma 2019 did not report data We assessed the certainty of evidence as low, downgraded two
for several listed outcomes, and Wang 2018 excluded infants who levels for very serious imprecision (Summary of findings 1).
were discharged from the analysis. Lavizzari 2016 had previously
reported interim outcome data from their trial prior to achieving Death (Analysis 1.2)
the planned sample size (Ciuffini 2014).
Meta-analysis of data from nine studies (2009 infants) suggests that
Other potential sources of bias use of nHF compared with CPAP may result in little to no difference
in death (Analysis 1.2).
Three studies reported continuous outcomes such as durations
of respiratory support, supplemental oxygen and hospitalisation • RR 0.78, 95% CI 0.44 to 1.39 (I2 = 0%)
as means and SD (Murki 2018; Nair 2005; Yoder 2013). Farhat • RD −0.01, 95% CI −0.02 to 0.01
2018 reported means but no SDs. The remaining studies reported
medians and interquartile ranges (IQRs) for continuous outcomes, We found no evidence of subgroup differences by gestation (Chi2 =
and these were converted to means and SD using the method 2.03, df = 2 (P = 0.36), I2 = 1.3%).
described by Wan 2014, and recommended by the Cochrane
Handbook for Systematic Reviews of Interventions (Higgins 2020). Subgroup analyses for heterogeneity
These outcome data may not have been normally distributed. Not applicable (I2 = 1.3%).
Effects of interventions Sensitivity analyses
See: Summary of findings 1 Nasal high flow compared to Risk of bias: not applicable (I2 = 1.3%).
continuous positive airway pressure for primary respiratory
support in preterm infants; Summary of findings 2 Nasal high flow Certainty of evidence (GRADE)
compared to nasal intermittent positive pressure ventilation for We assessed the certainty of evidence as low, downgraded two
primary respiratory support in preterm infants levels for very serious imprecision (Summary of findings 1).
Comparison 1. Nasal high flow compared with continuous Bronchopulmonary dysplasia (Analysis 1.3)
positive airway pressure for primary respiratory support in
preterm infants Meta-analysis of data from eight studies (1917 infants) suggests that
use of nHF compared with CPAP may result in little to no difference
See Summary of findings 1. in BPD (Analysis 1.3).
We included 11 studies (total 2196 infants) in this comparison • RR 1.14, 95% CI 0.74 to 1.76 (I2 = 0%)
(Armanian 2019; Demirel 2019; Farhat 2018; Lavizzari 2016; Manley • RD 0, 95% CI −0.01 to 0.02
2019; Nair 2005; Murki 2018; Roberts 2016; Sharma 2019; Shin 2017;
Yoder 2013). Shin 2017 did not report a time frame for the outcomes We found no evidence of subgroup differences by gestation (Chi2 =
of treatment failure and mechanical ventilation, therefore, we did 1.11, df = 2 (P = 0.57), I2 = 0%).
not include the data; however, these findings were consistent with
the results of the meta-analysis. Nair 2005 reported both treatment Subgroup analyses for heterogeneity
failure and mechanical ventilation at seven days, not 72 hours, Not applicable (I2 = 0%).
therefore, the data were not included; in this study, equal numbers
of infants in each arm required mechanical ventilation at seven Sensitivity analyses
days.
Risk of bias: not applicable (I2 = 0%).
Primary outcomes
Certainty of evidence (GRADE)
Death or bronchopulmonary dysplasia (Analysis 1.1)
We assessed the certainty of evidence as low, downgraded two
Meta-analysis of data from seven studies (1830 infants) suggests levels for very serious imprecision (Summary of findings 1).
that the use of nHF compared with CPAP may result in little to no
difference in death or BPD (Analysis 1.1). Treatment failure (as defined in the included studies) within 72 hours
of trial entry (Analysis 1.4)
• RR 1.09, 95% CI 0.74 to 1.60 (I2 = 0%) Meta-analysis of data from nine studies (2042 infants) suggests that
• RD 0, 95% CI −0.02 to 0.02 use of nHF compared with CPAP likely results in an increase in
treatment failure within 72 hours of trial entry (Analysis 1.4).
We found no evidence of subgroup differences by gestation (Chi2 =
1.62, degrees of freedom (df) = 2 (P = 0.45), I2 = 0%). • RR 1.70, 95% CI 1.41 to 2.06 (I2 = 36%)
Subgroup analyses for heterogeneity
• RD 0.09, 95% CI 0.06 to 0.12
• NNTH 11, 95% CI 8 to 17
Not applicable (I2 = 0%).
On subgroup analysis by GA, there was no difference between the
Sensitivity analyses subgroups (test for subgroup differences comparing 28 to 32 weeks'
Risk of bias: not applicable (I2 = 0%). GA and 32 weeks' GA or greater: P = 0.58, I2 = 0%).
Informed decisions.
Subgroup analyses for heterogeneity associated with a reduced risk of pneumothorax, compared with
Not applicable (I2 = 0%). CPAP (RR 0.48, 95% CI 0.23 to 1.00; RD −0.02, 95% CI −0.04 to 0.00;
5 studies, 1220 infants; Analysis 1.18). Other secondary outcomes
Sensitivity analyses were similar between groups, including mechanical ventilation at
any time point after trial entry (Analysis 1.6), duration of oxygen
Risk of bias: not applicable (I2 = 0%). supplementation (Analysis 1.8), surfactant treatment (Analysis
Certainty of evidence (GRADE) 1.9), duration of hospitalisation (Analysis 1.10), nosocomial sepsis
(Analysis 1.13), gastrointestinal perforation or severe NEC (Analysis
We assessed the certainty of evidence as moderate, downgraded 1.14), time to full feeds (Analysis 1.15), and ROP (Analysis 1.16). No
one level for serious risk of bias (Summary of findings 1). studies reported other individual air leak syndromes or long-term
neurodevelopmental outcomes.
Nair 2005 only reported treatment failure at seven days, and Shin
2017 did not report a time frame for treatment failure, therefore Comparison 2. Nasal high flow compared with nasal
we excluded the data from these studies. Five studies provided intermittent positive pressure ventilation for primary
data for GA subgroups (Lavizzari 2016; Manley 2019; Murki 2018; respiratory support in preterm infants
Roberts 2016; Yoder 2013). There were very few infants of less than
28 weeks' GA included in any study. See Summary of findings 2.
Mechanical ventilation via an endotracheal tube within 72 hours of We included four studies (total 343 infants) in this comparison
trial entry (Analysis 1.5) (Armanian 2019; Farhat 2018; Kugelman 2015; Wang 2018).
Meta-analysis of data from nine studies (2042 infants) suggests Primary outcomes
that the use of nHF compared with CPAP likely does not increase
mechanical ventilation within 72 hours of trial entry (Analysis 1.5). Death or bronchopulmonary dysplasia (Analysis 2.1)
Meta-analysis of data from two studies (total 182 infants) suggests

• RR 1.04, 95% CI 0.82 to 1.31 that the use of nHF compared with NIPPV may have little to no effect
• RD 0.00, 95% CI −0.02 to 0.03 on death or BPD but the evidence is very uncertain (Analysis 2.1).
We found no evidence of subgroup differences by gestation (Chi2 = • RR 0.64, 95% CI 0.30 to 1.37
3.32, df = 2 (P = 0.19), I2 = 39.7%). • RD −0.05, 95% CI −0.14 to 0.04
Subgroup analyses for heterogeneity
We found no evidence of subgroup differences by gestation (Chi2 =
Not applicable (I2 = 39.7%). 2.92, df = 3 (P = 0.40), I2 = 0%).
Sensitivity analyses Subgroup analyses for heterogeneity
Risk of bias: not applicable (I2 = 39.7%). Not applicable (I2 = 0%).
Certainty of evidence (GRADE) Sensitivity analyses
We assessed the certainty of evidence as moderate, downgraded Risk of bias: not applicable (I2 = 0%).
one level for serious risk of bias (Summary of findings 1).
On subgroup analysis, there was no difference in the risk of We assessed the certainty of evidence as very low, downgraded two
mechanical ventilation when trials that permitted surfactant use levels for very serious imprecision and one level for serious risk of
via INSURE during the intervention period were excluded (RR 1.19, bias (Summary of findings 2).
95% CI 0.86 to 1.66; 3 studies, 1068 infants; Analysis 1.17). There was
no difference in the risk of mechanical ventilation when trials that Death (Analysis 2.2)
permitted second-line CPAP during the intervention period were
Meta-analysis of data from three studies (254 infants) suggests that
excluded (RR 0.86, 95% 0.62 to 1.20; 6 studies, 827 infants; Analysis
the use of nHF compared with NIPPV may result in little to no
1.19). Five studies provided data for GA subgroups (Lavizzari 2016;
difference in death (Analysis 2.2).
Manley 2019; Murki 2018; Roberts 2016; Yoder 2013).
• RR 0.78, 95% CI 0.36 to 1.69
Secondary outcomes
• RD −0.02, 95% CI −0.10 to 0.05
The use of nHF as primary respiratory support, compared with
CPAP, likely results in a reduction in nasal trauma (RR 0.49, 95% CI We found no evidence of subgroup differences by gestation (Chi2 =
0.36 to 0.68; RD −0.06, 95% CI −0.09 to −0.04; 7 studies, 1595 infants; 0.27, df = 3 (P = 0.97), I2 = 0%).
moderate-certainty evidence; Analysis 1.12). Infants managed with
nHF had a longer duration of respiratory support (MD 0.52 days, Subgroup analyses for heterogeneity
95% CI 0.25 to 0.80; 7 studies, 1808 infants; Analysis 1.7). nHF Not applicable (I2 = 0%).
probably reduces pneumothorax compared with CPAP (RR 0.66,
95% CI 0.40 to 1.08; 10 studies, 2094 infants; moderate-certainty Sensitivity analyses
evidence; Analysis 1.11). A subgroup analysis excluding trials Risk of bias: not applicable (I2 = 0%).
which permitted surfactant use via INSURE during the intervention
period indicated that, without surfactant availability, nHF use was
Informed decisions.
Certainty of evidence (GRADE) Subgroup analyses for heterogeneity
We assessed the certainty of evidence as low, downgraded two Not applicable (I2 = 0%).
levels for very serious imprecision (Summary of findings 2).
Sensitivity analyses
Bronchopulmonary dysplasia (Analysis 2.3)
Meta-analysis of data from three studies (271 infants) suggests that
the use of nHF compared with NIPPV may result in little to no Certainty of evidence (GRADE)
difference in BPD (Analysis 2.3). We assessed the certainty of evidence as moderate, downgraded
one level for serious risk of bias (Summary of findings 2).
• RR 1.19, 95% CI 0.66 to 2.12
• RD 0.02, 95% CI −0.05 to 0.10 Data on any primary outcome for GA subgroups were available in
Kugelman 2015 and Wang 2018. Kugelman 2015 was the only study
We found no evidence of subgroup differences by gestation (Chi2 = to enrol extremely preterm infants born less than 28 weeks' GA;
1.65, df = 3 (P = 0.65), I2 = 0%). however, there were only three such infants included.
Subgroup analyses for heterogeneity Secondary outcomes
Not applicable (I2 = 0%). The use of nHF as primary respiratory support, compared with
Sensitivity analyses NIPPV, likely results in a reduction in nasal trauma (RR 0.21,
95% CI 0.09 to 0.47; RD −0.17, 95% CI −0.24 to −0.10; 3
Risk of bias: not applicable (I2 = 0%). studies, 272 infants; moderate-certainty evidence) (Analysis 2.10).
There were no differences in other secondary outcomes between
groups, including mechanical ventilation at any time after trial
We assessed the certainty of evidence as low, downgraded two entry (Analysis 2.6), surfactant treatment (Analysis 2.7), duration
levels for very serious imprecision (Summary of findings 2). of hospitalisation (Analysis 2.8), pneumothorax (Analysis 2.9),
nosocomial sepsis (Analysis 2.11), gastrointestinal perforation or
Treatment failure (Analysis 2.4) severe NEC (Analysis 2.12), or time to full feeds (Analysis 2.13). When
Meta-analysis of data from four studies (343 infants) suggests that study authors reported only medians for continuous data, and were
the use of nHF compared with NIPPV likely results in little to unable to provide means (SD), we had planned to calculate the
no difference in treatment failure within 72 hours of trial entry means using the method described by Wan 2014, as recommended
(Analysis 2.4). by the Cochrane Handbook for Systematic Reviews of Interventions
(Higgins 2020). However, only one study reported duration of
• RR 1.27, 95% CI 0.90 to 1.79 respiratory support (Analysis 2.14) or duration of supplemental
• RD 0.06, 95% CI −0.03 to 0.15 oxygen (Analysis 2.15); it was not possible to ascertain whether
these outcomes were normally distributed and therefore accurately
We found no evidence of subgroup differences by gestation (Chi2 = able to be converted to means. Kugelman 2015 reported duration
1.65, df = 3 (P = 0.65), I2 = 0%). of respiratory support to be a median of four days (IQR 1 to 15) in
the nHF group compared to two days (IQR 0.3 to 6.5) in the NIPPV
Subgroup analyses for heterogeneity group. Wang 2018 reported duration of supplemental oxygen as a
Not applicable (I2 = 0%). median of 13.7 days (IQR 4.9 to 29) in the nHF group, compared to
12.6 days (IQR 5.4 to 25.8) in the NIPPV group.
Sensitivity analyses
No studies reported long-term neurodevelopmental outcomes.
Comparison 3. Nasal high flow compared with ambient oxygen
No studies examined this comparison.
We assessed the certainty of evidence as moderate, downgraded
one level for serious risk of bias (Summary of findings 2). Comparison 4. Nasal high flow compared with low-flow nasal
cannulae
Mechanical ventilation (Analysis 2.5)
Meta-analysis of data from four studies (343 infants) suggests that No studies examined this comparison.
the use of nHF compared with NIPPV likely results in little to no
DISCUSSION
difference in mechanical ventilation within 72 hours of trial entry
(Analysis 2.5). Summary of main results
• RR 0.91, 95% CI 0.62 to 1.33 We included 13 RCTs (2540 preterm infants) that compared nHF
• RD −0.02, 95% CI −0.11 to 0.06 with other forms of non-invasive respiratory support for primary
respiratory support. Nine studies compared nHF with CPAP for
We found no evidence of subgroup differences by gestation (Chi2 = primary respiratory support, two studies compared nHF with NIPPV
0.09, df = 3 (P = 0.99), I2 = 0%). and two studies compared nHF with both CPAP and NIPPV. Studies
varied in the GA of included infants, the nHF gas flows used and the
devices used. They also differed regarding the approach to the use
Informed decisions.
of surfactant, and the use of other respiratory support modalities in study and therefore conclusions cannot be drawn regarding the use
the event of treatment failure. of nHF in this population.
When compared with CPAP for primary respiratory support in Quality of the evidence
preterm infants, nHF may result in little to no difference in the rate
of death or BPD (low-certainty evidence). We found that compared The overall certainty of evidence comparing nHF with CPAP
with CPAP, the use of nHF likely results in an increase in treatment was rated using GRADE as low to moderate. The outcomes of
failure (moderate-certainty evidence), but not of endotracheal treatment failure, mechanical ventilation and nasal trauma were
intubation and mechanical ventilation within 72 hours of trial downgraded due to serious concerns regarding risk of bias (lack
entry (moderate-certainty evidence), with no difference between of blinding of the intervention arms). The outcomes of death and
the GA subgroups. Subgroup analyses showed similar rates of BPD were downgraded due to very serious concerns regarding
mechanical ventilation between groups after excluding trials in imprecision, due to the low event rate and wide CIs. The outcome
which surfactant was permitted, and in which second-line CPAP of pneumothorax was also downgraded due to serious concerns
was permitted. regarding imprecision, relating to the low event rate.
nHF likely results in a reduction in nasal trauma compared with Potential biases in the review process
CPAP (moderate-certainty evidence). nHF was associated with an We made the judgement to divide the previous review of nHF
approximately half day longer duration of respiratory support; in preterm infants into two, given the increase in the number
the clinical significance of this is uncertain and may depend of studies. This current review outlines the evidence for nHF
on local resources. The rate of pneumothorax was likely lower as primary respiratory support (prior to mechanical ventilation
with the use of nHF, compared with CPAP (moderate-certainty or surfactant provision via an endotracheal tube). Studies were
evidence). In trials where surfactant use was not permitted during included in this review if the main intent of the trial was the
the intervention period, the rate of pneumothorax was also lower provision of nHF for primary respiratory support; we resolved any
in babies managed with nHF. Other secondary outcomes including uncertainties by consensus agreement if required. Iranpour 2012
durations of supplemental oxygen and hospitalisation and sepsis was included in the primary support section of the original review
were similar between groups. (Wilkinson 2011), and the 2016 update (Wilkinson 2016), but not
this version following communication from the authors suggesting
When compared with NIPPV for primary respiratory support in
that the randomisation occurred after surfactant provision. We
preterm infants, nHF may have little to no effect on death or BPD
amended the time frame for the outcomes of treatment failure and
but the evidence is very uncertain. nHF likely results in no difference
mechanical ventilation for this review. This was a decision made
in treatment failure or mechanical ventilation within 72 hours of
following selection of the studies, given that all but one study which
trial entry, compared with NIPPV. nHF likely results in a reduction in
reported the outcomes (Nair 2005) did so at 72 hours, rather than
nasal trauma, but other secondary outcomes were similar between
seven days (the time frame in the previous version of the review).
groups.
The exclusion of the data from Nair 2005 is a potential bias; we have
Overall completeness and applicability of evidence therefore described the findings for these outcomes in the text.
The 13 included studies varied in quality. None of the studies were The protocol and earlier versions of this review included Embase
blinded; while all studies except Sharma 2019 had prespecified as a search source. This update omitted Embase based on the
criteria for treatment failure and reintubation, the lack of blinding rationale that CENTRAL now includes records from Embase. This
may have led to some bias. We did not perform a sensitivity analysis rationale has, subsequently, been flagged as a method that may
for study quality. reduce sensitivity of the search. Subsequent updates will include
Embase as a source.
Four trials permitted the use of CPAP in infants who met nHF
treatment failure criteria (Manley 2019; Murki 2018; Roberts 2016; Agreements and disagreements with other studies or
Shin 2017). Two studies also permitted the use of BiPAP in reviews
infants who met CPAP failure criteria (Lavizzari 2016; Shin 2017).
A subgroup analysis excluding trials in which 'rescue' CPAP was The results of our review are in agreement with a rapid systematic
permitted in the event of nHF treatment failure found similar rates review (Conte 2018) and systematic review (Bruet 2021), and in
of mechanical ventilation. contrast to the conclusions of the previous version of this review
(Wilkinson 2016), given the large number of different included
Furthermore, the approach to surfactant therapy differed between studies of high flow for primary respiratory support.
studies. Five studies permitted the use of surfactant via the
INtubation, SURfactant, Extubation (INSURE) technique without AUTHORS' CONCLUSIONS
this being deemed treatment failure (Armanian 2019; Demirel 2019;
Farhat 2018; Lavizzari 2016; Murki 2018). The success or failure
Implications for practice
of non-invasive respiratory support may differ in infants with We found that the use of nasal high flow (nHF) for primary
atelectatic, surfactant-deplete lungs, compared with surfactant- respiratory support in preterm infants of 28 weeks' gestation
replete lungs. or greater may result in little to no difference in the clinically
important outcomes of death or bronchopulmonary dysplasia
Overall, most studies reported the primary outcomes of this review. (BPD), compared with continuous positive airway pressure (CPAP)
No studies reported long-term neurodevelopmental outcomes, or nasal intermittent positive pressure ventilation (NIPPV). The
such as cerebral palsy or developmental delay. Very few extremely overall certainty of evidence for the outcomes of death and BPD
preterm infants less than 28 weeks' gestation were included in any
Informed decisions.
was very low to low. The use of nHF likely results in an increase in ACKNOWLEDGEMENTS
treatment failure within 72 hours of trial entry, but no difference
in the rate of endotracheal intubation and mechanical ventilation, We acknowledge Chad Andersen and Colm O'Donnell as authors on
where there is the option of surfactant or CPAP (or both) in the event previous versions of this review.
of nHF treatment failure.
We are grateful to authors who provided additional data from
Compared with CPAP, nHF likely results in a reduction in nasal their studies, in particular Dr Ma Li and Dr Cuiqing Liu, Dr Ramin
trauma and likely a reduction in pneumothorax. There may be a Iranpour, Dr Bradley Yoder, Professor Hesham Abdel-Hady, Dr Amir
small increase in the total duration of respiratory support in infants Kugelman, Dr Clare Collins, Dr Gharehbaghi, Dr Nair, Dr Calum
treated with nHF. There is insufficient evidence to guide the use of Roberts, Dr Gaston Arnolda, Dr Anna Lavizzari and Dr Srinivas Murki.
nHF in extremely preterm infants of less than 28 weeks' gestation Dr Wei Ling Lean and Dr Wei Qi Fan assisted with translation of two
based on this review. of the papers.
Implications for research We would like to thank Cochrane Neonatal: Michelle Fiander, Fiona
Russell and Jane Cracknell Managing Editors; and Roger Soll and
There are nine studies awaiting classification and 13 ongoing Bill McGuire, Co-coordinating Editors who provided editorial and
studies. Future trials should focus on investigating novel uses of administrative support. We thank Carol Friesen, former Information
nHF for neonates, including using higher gas flows than current Specialist with Cochrane Neonatal for writing search strategies; and
standard practice, in combination with less-invasive surfactant Michelle Fiander for running them in 2022.
administration, during neonatal endotracheal intubation, and for
delivery room stabilisation of preterm infants. Few of the current We acknowledge Geoff Hill, Royal Melbourne Hospital librarian, for
ongoing studies will investigate these areas. There is a need for conducting a previous search.
studies evaluating the use of nHF as primary support in extremely
preterm infants born less than 28 weeks' gestation and also Jacqueline Ho and María Ximena Rojas peer reviewed and offered
comparing commercially available devices. feedback for this review.
Standardised definitions of nHF flows and treatment failure (with We thank Heather Maxwell for copy editing the manuscript.
predefined criteria for hypoxia, hypercarbia and apnoea) should be
employed in future studies.
Informed decisions.
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Lee 2011 {published data only} Shokouhi 2019 {published data only}
Lee EH, Choi BM, Park KH, Park C, Park HJ, Hwang MJ, et al. Shokouhi M, Basiri B, Sabzehei MK, Mahdiankhoo M,
Comparing humidified high Flow nasal cannula (HHFNC) Pirdehghan A. Efficacy and complications of humidified high-
versus nasal continuous positive airway pressure (NCPAP) flow nasal cannula versus nasal continuous positive airway
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Humidified High-flow Nasal Cannula Ventilation. Efficacy Soonsawad S, Tongsawang N, Nuntnarumit P. Heated
and safety of heated humidified high-flow nasal cannula for humidified high-flow nasal cannula for weaning from
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of nasal continuous positive airway pressure (NCPAP) and high Comparing two methods of delivering high-flow gas therapy by
flow nasal cannula (HFNC) in prevention of post extubation nasal cannula following endotracheal extubation: a prospective,
assisted ventilation. Zahedan Journal of Research in Medical randomized, masked, crossover trial. Journal of Perinatology
Sciences 2015;17(6):e984. [DOI: 10.17795/zjrms984] 2006;26(8):481-5. [DOI: 10.1038/sj.jp.7211543] [PMID: 16724119]
Nasef 2015 {published data only} Zivanovic 2019 {published data only}
Nasef N, El-Gouhary E, Schurr P, Reilly M, Beck J, Dunn M, et Zivanovic S, Scrivens A, Panza R, Reynolds P, Laforgia N,
al. High-flow nasal cannulae are associated with increased Ives KN, et al. Nasal high-flow therapy as primary respiratory
diaphragm activation compared with nasal continuous support for preterm infants without the need for rescue with
positive airway pressure in preterm infants. Acta Paediatrica nasal continuous positive airway pressure. Neonatology
2015;104(8):e337-43. [DOI: 10.1111/apa.12998] [PMID: 2019;115(2):175-81. [DOI: 10.1159/000492930] [PMID: 30513521]
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Pyon 2008 {published data only} References to studies awaiting assessment

Pyon KH, Aghai ZH, Nakhla TA, Stahl GE, Saslow JG. High flow Awad 2021 {published data only}
nasal cannula in preterm infants: effects of high flow rates on
Awad HA, El-Farrash RA, Shinkar DM, Aly YA, Soliman N,
work of breathing. In: Proceedings of the Pediatric Academic
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cannula as an initial respiratory support in preterm neonates.
PAS2008:633763.13.
QJM : An International Journal of Medicine 2021;114:Suppl 1.
Saslow 2006 {published data only}
Balasubramanian 2022 {published data only}
* Saslow JG, Aghai ZH, Nakhla TA, Hart JJ, Lawrysh R, Stahl GE,
Balasubramanian H, Sakharkar S, Majarikar S, Srinivasan L,
et al. Work of breathing using high-flow nasal cannula in
Kabra NS, Garg B, et al. Efficacy and safety of two different flow
preterm infants. Journal of Perinatology 2006;26(8):476-80.
rates of nasal high-flow therapy in preterm neonates ≥28 weeks
[DOI: 10.1038/sj.jp.7211530] [PMID: 16688202]
Informed decisions.
of gestation: a randomized controlled trial. American Journal of ACTRN12611000233921 {published data only}
Perinatology 2022;39(15):1693-701. ACTRN12611000233921. The use of headbox oxygen versus high
flow nasal cannula (HFNC) for neonatal respiratory distress
Cetinkaya 2018 {published data only (unpublished sought but not
in non-tertiary hospitals [High-flow nasal cannulae versus
used)}
ambient oxygen for the treatment of newborn infants with early
Cetinkaya M, Cebeci B, Semerci S Y, Kurnaz D, Saglam O. respiratory distress in non-tertiary special care nurseries – a
Comparison of three different non-invasive ventilation modes in multicentre randomised controlled trial]. anzctr.org.au/Trial/
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randomized study. 26th European Workshop on Neonatology; February 2011).
2018 Sep 2–5; Cappadocia, Turkey. [content.iospress.com/
download/journal-of-neonatal-perinatal-medicine/ CTRI/2017/09/009910 {published data only}
npm189001?id=journal-of-neonatal-perinatal-medicine CTRI/2017/09/009910. High flow nasal cannulae versus
%2Fnpm189001] nasal continuous positive airway pressure in neonates with
respiratory distress syndrome [To study the equivalence
Febre 2015 {published data only}
of high flow nasal cannula oxygen therapy and nasal
Febre A, Merritt TA, Terry M, Tong C, Goldstein M. Adaptive continuous positive airway pressure as respiratory
dynamic inspiratory nasal apparatus: comparison to traditional support in preterm neonates – a prospective observational
nasal continuous airway pressure (NCPAP). Newborn and study]. ctri.nic.in/Clinicaltrials/pdf_generate.php?
Infant Nursing Reviews 2015;15(1):17-20. [DOI: 10.1053/ trialid=13233&EncHid=&modid=&compid=%27,%2713233det
j.nainr.2015.01.008] %27 (first received 25 September 2017).
Iskandar 2019 {published data only} CTRI/2019/10/021633 {published data only}
Iskandar A, Kaban R, Djer M. Heated, humidified high-flow nasal CTRI/2019/10/021633. Breathing stabilization in small
cannula vs. nasal CPAP in infants with moderate respiratory babies at the time of birth [Delivery room respiratory
distress. Paediatrica Indonesiana 2019;59(6):331. stabilization of preterm neonates: a randomized controlled
trial]. ctri.nic.in/Clinicaltrials/pdf_generate.php?
Lawrence 2012 {published data only}
trialid=37352&EncHid=&modid=&compid=%27,%2737352det
Lawrence JR, Martin GC. A pilot study to evaluate the safety %27 (first received 14 October 2019).
and efficacy of high flow nasal cannula vs. conventional NCPAP.
Pediatric Academic Society; 2012 Apr 28-May 1; Boston (MA). Irct2016052510026N {published data only}
Irct2016052510026N. Therapeutic effect of heated,
Oktem 2021 {published data only}
humidified, high-flow nasal cannula (HHHFNC) in respiratory
Oktem A, Yigit S, Celik HT, Yurdakok M. Comparison of four distress syndrome. trialsearch.who.int/Trial2.aspx?
different non-invasive respiratory support techniques as TrialID=IRCT2016052510026N7 (first received 31 March 2019).
primary respiratory support in preterm infants. Turkish Journal [CENTRAL: CN-01895122]
of Pediatrics 2021;63(1):23-30.
Irct20180226038865N {published data only}
Park 2011 {published data only}
Irct20180226038865N. Comparison of two forms of non-invasive
Park KH, Lee EH, Chung BH, Choi YO, Lee JH, Choi BM, et al. respiratory supporting preterm infants. trialsearch.who.int/
Comparing usefulness of humidified high-flow nasal cannula Trial2.aspx?TrialID=IRCT20180226038865N1 (first received 31
and nasal continuous positive airway pressure for neonatal March 2019). [CENTRAL: CN-01895352]
respiratory diseases in preterm infants. Pediatric Academic
Societies Annual Meeting; 2011 Apr 30–May 3; Denver, CO. Irct20190623043988N {published data only}
[CENTRAL: CN-00831960] Continuous positive airway pressure or high flow nasal
cannula for respiratory distress syndrome. trialsearch.who.int/
Shirvani 2019 {published data only}
Trial2.aspx?TrialID=IRCT20190623043988N1 (first received 5
Shirvani TE, Nayeri FS, Shariat M, Nafas NN, Mirjalili SR, July 2019).
Hosseini SN, et al. Continuous positive airway pressure or
high flow nasal cannula for respiratory distress syndrome: a Irct20200616047788N {published data only}
randomized control trial among premature infants. Research Irct20200616047788N. Comparing two respiratory support
Square 2019 [Preprint]. [DOI: 10.21203/rs.2.11296/v1] methods in RDS treatment of premature neonates.
trialsearch.who.int/Trial2.aspx?TrialID=IRCT20200616047788N1
(first received 21 July 2020).
References to ongoing studies
ACTRN12610000677000 {published data only} ISRCTN66716753 {published data only}
ACTRN12610000677000. High flow support versus continuous ISRCTN66716753. High flow nasal prongs (HFNP) therapy
positive airway pressure (CPAP) support in non-acute versus nasal continuous positive airway pressure (NCPAP) in
respiratory support for preterm infants from 30 weeks establishing full oral feeds in very low birth weight (VLBW)
corrected gestation. who.int/trialsearch/Trial2.aspx? infants – randomized controlled trial [Can high flow nasal
TrialID=ACTRN12610000677000 (first received 18 August 2010). prongs therapy facilitate earlier establishment of full oral
feeds in babies who are nasal continuous positive airway
Informed decisions.
pressure dependent at 32 weeks gestation?]. isrctn.com/ Fetal and Neonatal Edition 2022;107(1):56-9. [DOI: 10.1136/
ISRCTN66716753 (first received 1 February 2013). archdischild-2020-321094]
NCT01270581 {unpublished data only} Ciuffini 2014

NCT01270581. High flow nasal cannula versus bubble nasal Ciuffini F, Pietrasanta C, Lavizzari A, Musumeci S, Gualdi C,
CPAP for the treatment of transient tachypnea of the newborn Sortino S, et al. Comparison between two different modes
in infants ≥ 35 weeks gestation. clinicaltrials.gov/ct2/show/ of non-invasive ventilatory support in preterm newborn
NCT01270581 (first received 5 January 2011). infants with respiratory distress syndrome mild to moderate:
preliminary data. La Pediatria Medica e Chirurgica 2014;36(4):88.
NCT02055339 {published data only} [DOI: 10.4081/pmc.2014.88]
NCT02055339. Comparison of nasal continuous positive airway
pressure with low flow oxygen versus heated, humidified Collins 2013a
high flow nasal cannula for oral feeding of the premature Collins CL, Holberton JR, König K. Comparison of the
infant (chomp trial): a pilot study [Pilot study comparing pharyngeal pressure provided by two heated, humidified high-
different modes of non-invasive ventilation for the oral feeding flow nasal cannulae devices in premature infants. Journal of
of preterm infants (CHOMP)]. clinicaltrials.gov/ct2/show/ Paediatrics and Child Health 2013;49(7):554-6. [DOI: 10.1111/
NCT02055339 (first received 5 February 2014). jpc.12277] [PMID: 23782410]
NCT02499744 {published data only} Conte 2018

NCT02499744. Humidified high flow nasal cannula versus nasal Conte F, Orfeo L, Gizzi C, Massenzi L, Fasola S. Rapid systematic
intermittent positive ventilation in neonates. clinicaltrials.gov/ review shows that using a high-flow nasal cannula is inferior to
ct2/show/NCT02499744 (first received 16 July 2015). nasal continuous positive airway pressure as first-line support
in preterm neonates. Acta Paediatrica 2018;107(10):1684-96.
UMIN000018983 {published data only} [DOI: 10.1111/apa.14396] [PMID: 29751368]
UMIN000018983. Effective and safe use of heated humidified
high flow nasal cannula in neonates. umin.ac.jp/cgi-open- Davidson 2017
bin/ctr_e/ctr_view.cgi?recptno=R000021932 (first received 29 Davidson LM, Berkelhamer SK. Bronchopulmonary dysplasia:
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preterm infants at birth: systematic review and meta-analysis.
BMJ 2013;347:f5980. [DOI: 10.1136/bmj.f5980] [PMID: 24136633] Wilkinson DJ, Andersen CC, Smith K, Holberton J. Pharyngeal
pressure with high-flow nasal cannulae in premature infants.
Schünemann 2013 Journal of Perinatology 2008;28(1):42-7. [DOI: 10.1038/
Schünemann H, Brożek J, Guyatt G, Oxman A, editor(s). sj.jp.7211879] [PMID: 17989697]
Handbook for grading the quality of evidence and the strength
of recommendations using the GRADE approach (updated
October 2013). GRADE Working Group, 2013. Available from References to other published versions of this review
gdt.guidelinedevelopment.org/app/handbook/handbook.html. Wilkinson 2007
Wilkinson D, Andersen C, O'Donnell CP. High flow nasal cannula
Shetty 2016
for respiratory support in preterm infants. Cochrane Database
Shetty S, Hickey A, Rafferty GF, Peacock JL, Greenough A. of Systematic Reviews 2007, Issue 1. Art. No: CD006405. [DOI:
Work of breathing during CPAP and heated humidified high- 10.1002/14651858.CD006405]
flow nasal cannula. Archives of Disease in Childhood. Fetal
and Neonatal Edition 2016;101(5):F404-7. [DOI: 10.1136/ Wilkinson 2011
archdischild-2015-309310] [PMID: 26769758] Wilkinson D, Andersen C, O'Donnell CP, De Paoli AG. High
flow nasal cannula for respiratory support in preterm infants.
Sivieri 2017
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Sivieri EM, Foglia EE, Abbasi S. Carbon dioxide washout during CD006405. [DOI: 10.1002/14651858.CD006405.pub2]
high flow nasal cannula versus nasal CPAP support: an in vitro
study. Pediatric Pulmonology 2017;52(6):792-8. [DOI: 10.1002/ Wilkinson 2016
ppul.23664] [PMID: 28165671] Wilkinson D, Andersen C, O'Donnell CP, De Paoli AG, Manley BJ.
High flow nasal cannula for respiratory support in preterm
Spence 2007
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Spence KL, Murphy D, Kilian C, McGonigle R, Kilani RA. Art. No: CD006405. [DOI: 10.1002/14651858.CD006405.pub3]
High-flow nasal cannula as a device to provide continuous
* Indicates the major publication for the study
CHARACTERISTICS OF STUDIES
Characteristics of included studies [ordered by study ID]
Armanian 2019
Study characteristics
Methods Randomised controlled trial
Participants 109 preterm neonates with BW < 1500 g; mean 30 weeks' GA
Interventions nHF (35 infants): 2.5 L/min for infants < 1000 g, 3 L/min for infants 1000–1500 g
Nasal CPAP (37 infants): pressure 5–6 cmH2O
NIPPV (37 infants): termed NIMV in this study, PIP 16–20 cmH2O, PEEP 5–6 cmH2O, rate 50 breaths/min,
inspiratory time 0.4 seconds
Outcomes • Treatment failure (based on prespecified criteria: pH < 7.2 and PCO2 > 60 mmHg, repeated or severe
apnoea, FiO2 > 40–60%, or requirement for emergency intubation).
• Surfactant
Informed decisions.
Armanian 2019 (Continued)

• Duration of respiratory support
• IVH
• PDA
• Pneumothorax
• Duration of supplemental oxygen
• Duration of hospitalisation
• Mortality
Notes Recruitment from February 2015 to March 2016 at 2 centres in Iran.
No funding stated, no conflicts of interest declared.
Infants in nHF group had a higher GA (approx 1 week) and higher BW (approx 130 g).
Infants received surfactant via INSURE if FiO2 > 0.3 to maintain SpO2 > 91%.
Registered trial protocol did not have CPAP group.
Risk of bias
Bias Authors' judgement Support for judgement
Random sequence genera- Low risk Permuted block randomisation (block size 6).
tion (selection bias)
Allocation concealment Unclear risk Envelopes containing names of therapy group (not stated whether opaque, se-
(selection bias) quentially numbered and sealed).
Blinding of participants Unclear risk Unblinded study.

and personnel (perfor-
mance bias)
Blinding of outcome as- Unclear risk Treatment failure criteria stated; however, large range for FiO2 and duration
sessment (detection bias) not stated, blood gas criteria unclear.
Mechanical ventilation
within 72 hours of trial en-
try
Incomplete outcome data Low risk Similar reasons for missing secondary outcome data across groups.
(attrition bias)
All outcomes
Selective reporting (re- High risk Trial registry did not have CPAP arm. Not all outcomes from trial registry re-
porting bias) ported in paper.
Other bias Low risk No other bias noted.
Demirel 2019
Participants 107 preterm infants ≤ 32 weeks' gestation with spontaneous respiration
Interventions nHF (54 infants): Vapotherm device, initial flow rate 6 L/min, up to a maximum of 8 L/min
Informed decisions.
Demirel 2019 (Continued)

Nasal CPAP (53 infants): SERVO-i ventilator, initial pressure 6 cmH2O, up to a maximum of 8 cmH2O
Outcomes Primary outcome
• Treatment failure, based on prespecified criteria:

◦ increase in work of breathing;
◦ apnoea/bradycardia/desaturation > 3 times in 1 hour;
◦ apnoea requiring positive pressure ventilation
◦ FiO2 > 0.6 to maintain SpO2 90% to 95%
◦ pH < 7.25 or pCO2 > 65 mmHg
Secondary outcomes
• Duration of non-invasive respiratory support

• Duration of oxygen therapy
• Maximum FiO2
• Duration of hospital stay
• Intubation
• Pneumothorax
• BPD
Notes Recruitment from February 2017 to February 2018 at 1 centre in Turkey.
All eligible infants ≤ 32 weeks' GA enrolled (did not need to have respiratory distress). Surfactant given
via INSURE if FiO2 > 0.4 and RDS on CXR.
Risk of bias
Random sequence genera- Low risk Computer-generated random number.

Allocation concealment Low risk Sequentially numbered sealed opaque envelopes containing group assign-
(selection bias) ments.

mance bias)
Blinding of outcome as- Unclear risk Caregivers unblinded to intervention. Treatment failure criteria specified;
sessment (detection bias) however, included a subjective assessment of increased 'work of breathing'
Mechanical ventilation and apnoea/bradycardia/desaturation.
try
Incomplete outcome data Unclear risk Insufficient reporting of attrition/exclusions to permit judgement.
(attrition bias)
All outcomes
Selective reporting (re- Unclear risk Unclear whether trial was registered prospectively.
porting bias)
Informed decisions.
Farhat 2018
Participants 160 preterm neonates 28–34+6 weeks' gestation; BW 800–2500 g with RDS
Interventions nHF therapy (54 infants): flow rate dependent upon weight (2–5 L/min)
Nasal CPAP (53 infants): initial pressure 6 cmH2O, maximum pressure 8 cmH2O
Nasal intermittent positive pressure ventilation (53 infants): initial PIP < 18 cmH2O, initial PEEP 4–5
cmH2O, rate and inspiratory time not stated
• Intubation and mechanical ventilation within 72 hours, based on prespecified criteria:

◦ severe apnoea
◦ PaCO2 > 60 mmHg
◦ pH < 7.2
◦ FiO2 > 0.5
Secondary outcomes
• Duration of mechanical ventilation

• Surfactant administration
• IVH
• Sepsis
• Air leak
• Pulmonary haemorrhage
• Nasal trauma
• BPD
• Death
Notes Recruitment from April 2014 to November 2014 at 1 centre in Iran.
Randomisation and consent processes not outlined. Unclear starting flow rates for nHF and uncertain
which devices used. Surfactant permitted via INSURE.
No data for the combined outcome of death or BPD.
Risk of bias
Random sequence genera- Unclear risk Stated to be 'randomised convenience sampling method.' Information about
tion (selection bias) sequence generation not available.
Allocation concealment High risk No description in paper.

(selection bias)
Informed decisions.
Farhat 2018 (Continued)

mance bias)
Blinding of outcome as- Unclear risk Criteria stated; however, 'severe apnoea' not defined.
sessment (detection bias)
try
Blinding of outcome as- High risk No description of assessment in paper.

Nasal trauma
(attrition bias)
All outcomes
Selective reporting (re- Unclear risk Trial not prospectively registered.

porting bias)
Kugelman 2015
Participants 76 preterm infants < 35 weeks' gestation, BW > 1000 g requiring primary respiratory support from birth
Interventions HFNC (38 infants): 1–5 L/min
Synchronised NIPPV via nasal prongs (38 infants): 12–30 cycles/min, inspiratory time of 0.3 seconds,
PEEP 6 cmH2O, and PIP 14–22 cmH2O
Outcomes • Treatment failure (increased respiratory distress plus respiratory acidosis (pH < 7.2, CO2 > 60 mmHg)
FiO2 > 0.50 or recurrent significant apnoea)
• Clinical features
• IVH
• BPD (oxygen at 36 weeks' PMA)
• Time until full feeds
• Length of stay
• Air leak
• Nasal trauma
• Gastrointestinal perforation
Notes Recruitment at 1 centre in Israel. Pilot study, underpowered to detect clinically significant difference in
outcomes between interventions. Time point for treatment failure not defined. Infants meeting failure
of treatment criteria in the HFNC arm were able to receive NIPPV. Treatment failure reported separate-
ly from reintubation. nHF equipment supplied by Vapotherm.
No external funding, no conflicts of interest declared.
Informed decisions.
Kugelman 2015 (Continued)
Risk of bias
Random sequence genera- Unclear risk 'Randomly prepared cards.' Process of sequence generation not described.
Allocation concealment Low risk Sealed envelopes.

(selection bias)

mance bias)
Blinding of outcome as- Unclear risk Unblinded study. Criteria stated.

try
Blinding of outcome as- High risk Unblinded assessment. Criteria not stated in main paper or protocol.
Nasal trauma
Incomplete outcome data Low risk No missing outcome data.

(attrition bias)
All outcomes
Selective reporting (re- Low risk Trial registered. All outcomes recorded in protocol reported.
porting bias)
Lavizzari 2016
Methods Randomised non-inferiority trial
Participants 316 preterm infants 29–36+6 weeks' GA with mild–moderate respiratory distress
Interventions nHF (158 infants): Vapotherm Precision Flow, initial flow rate 4–6 L/min, maximum flow rate 6 L/min
Nasal CPAP (158 infants): SiPAP, Viasys Healthcare, initial pressure 4–6 cmH2O, maximum pressure 6
cmH2O
• Mechanical ventilation (excluding INSURE) within 72 hours, based on prespecified criteria:

◦ FiO2 > 0.4 to maintain SpO2 86–93%
◦ > 4 episodes apnoea per hour or > 2 requiring positive pressure ventilation
◦ pH < 7.20
◦ PaCO2 > 70 mmHg
Secondary outcomes
Informed decisions.
Lavizzari 2016 (Continued)

• Surfactant treatment
• Days to reach full enteral feeds
• Pneumothorax
• IVH
• PDA
• Sepsis
• NEC
• BPD
• ROP
• Death
Notes Recruitment from 5 January 2012 to 28 June 2014 at 1 centre in Italy.
Surfactant permitted prior to reaching treatment failure criteria, administered via INSURE if FiO2 > 0.35
to maintain SpO2 86–93%.
BiPAP also permitted in CPAP arm if apnoea or increased work of breathing.
Trial not registered prior to commencement.
Preliminary publication of some results prior to trial completion. Further outcome data for GA sub-
groups provided by study authors.
Risk of bias
Random sequence genera- Low risk Block randomisation.

Allocation concealment Low risk Sequentially numbered, sealed, opaque envelopes.

(selection bias)

mance bias)
Blinding of outcome as- Unclear risk Unblinded study with prespecified criteria for treatment failure; however,
sessment (detection bias) some subjectivity, e.g. definition of 'persistent' oxygen requirement or respira-
Mechanical ventilation tory acidosis.
try

(attrition bias)
All outcomes
Selective reporting (re- Unclear risk Trial only registered after completion of recruitment. Preliminary publication
porting bias) of results prior to trial completion.
Other bias Unclear risk Preliminary publication of results (Ciuffini 2014).
Informed decisions.
Manley 2019
Participants 754 infants (379 preterm infants 31–36+6 weeks' GA and BW > 1200 g) with respiratory distress in non-
tertiary special care units
Interventions nHF (185 infants): Fisher & Paykel Optiflow Junior, initial gas flow 6 L/min, maximum gas flow 8 L/min
Nasal CPAP (194 infants): binasal prongs or nasal mask: initial pressure 6 cmH2O, maximum pressure 8
cmH2O
• Treatment failure within 72 hours, based on prespecified criteria:

◦ maximal support plus FiO2 ≥ 0.4
◦ pH ≤ 7.2
◦ pCO2 > 60 mmHg
◦ ≤ 2 episodes of apnoea requiring positive pressure ventilation within 24 hours or 6 episodes requir-
ing any intervention within 6 hours
◦ urgent need for intubation or NICU transfer as determined by treating clinician
Secondary outcomes
• Reasons for treatment failure

• Intubation
• Transfer to tertiary NICU
• Surfactant
• Duration of respiratory support and supplemental oxygen
• Hospital stay
• Death before hospital discharge
• BPD
• Pneumothorax
• Cost of care
Notes Recruitment from 13 April 2015 to 28 November 2017 at 9 non-tertiary special-care nurseries in Aus-
tralia.
Funded by Australian National Health and Medical Research Council and Monash University.
No conflicts of interest declared in publication. Lead author is also an author on this Cochrane Review
(BJM).
Infants assigned to nHF arm who met treatment failure criteria could receive CPAP as a rescue therapy.
Surfactant not permitted prior to intubation.
Further outcome data for GA subgroups provided by study authors.
Risk of bias
Random sequence genera- Low risk Computer-generated randomisation sequence with variable block sizes.
Informed decisions.
Manley 2019 (Continued)
Allocation concealment Low risk Sequentially numbered, sealed, opaque envelopes.

(selection bias)

mance bias)
Blinding of outcome as- Unclear risk Unblinded study. Treatment failure criteria prespecified; however, some sub-
sessment (detection bias) jectivity, e.g. included urgent need for intubation as per treating clinician.
try
Blinding of outcome as- Unclear risk Assessor not blinded to treatment group, but objective criteria for assessment.
Nasal trauma

(attrition bias)
All outcomes
Selective reporting (re- Low risk Trial registered and all outcomes reported.
porting bias)
Murki 2018
Participants 272 preterm infants 28–36+6 weeks' GA and BW > 1000 g with respiratory distress in 2 centres in India
Interventions nHF (133 infants): Fisher & Paykel Optiflow Junior or AIRVO 2, initial flow rate 5 L/min, maximum 7 L/
min
Nasal CPAP (139 infants): Fisher & Paykel, binasal prongs or mask, initial pressure 5 cmH2O, maximum
pressure 7 cmH2O
• Treatment failure within 72 hours of life, based on prespecified criteria:

◦ maximal support and FiO2 > 0.6
◦ pH < 7.20
◦ PaCO2 > 60 mmHg
◦ increase in Silverman Anderson score
◦ recurrent apnoea (4 per hour or any requiring positive pressure ventilation)
◦ shock
Secondary outcomes
• Mechanical ventilation within 72 hours of life

• Mechanical ventilation within 7 days of life
• Surfactant
Informed decisions.
Murki 2018 (Continued)

• Mortality
• Pneumothorax
• Culture-positive sepsis
• NEC Bell Stage ≥ II
• Nasal injury
• BPD
• Grade III/IV IVH
• Cystic PVL
• ROP
• Time to full feeds
• Weight at discharge
Notes Recruitment from 9 October 2015 to 26 November 2016 at 2 centres in India.
No funding stated, no conflicts of interest disclosed.
Rescue CPAP permitted in nHF group following treatment failure, prior to intubation. Surfactant per-
mitted via INSURE if RDS on CXR and FiO2 > 0.3.
Incorrect sample size calculation. Trial registration stated different sample size to final paper.
Risk of bias
Random sequence genera- Low risk Computer-generated randomisation.

Allocation concealment Low risk Serially numbered, opaque, sealed envelopes.

(selection bias)

mance bias)
Blinding of outcome as- Unclear risk Unblinded study, prespecified treatment failure criteria but some subjectivity
sessment (detection bias) with interpretation (e.g. duration of increased FiO2).
try
Blinding of outcome as- Unclear risk Assessor not blinded to intervention arm but objective scoring method.
Nasal trauma

(attrition bias)
All outcomes
Selective reporting (re- Unclear risk Trial prospectively registered but discrepancies between registration and final
porting bias) protocol.
Informed decisions.
Murki 2018 (Continued)
Nair 2005
Participants 67 preterm infants with respiratory distress requiring CPAP in 1st 6 hours, 27–34 weeks' GA (mean 32
weeks)
Interventions HFNC (33 infants): Vapotherm 5–6 L/min
CPAP (34 infants): bubble CPAP, Hudson prongs, 5–6 cmH2O
Outcomes • Respiratory failure (leading to intubation) (pH ≤ 7.25 and PaCO2 ≥ 60 mmHg, or FiO2 > 0.70, or severe
or frequent apnoea)
• Nasal injury
• BPD (as defined in Jobe 2001)
• Mortality
• Length of hospitalisation
• Sepsis
• Pneumothorax
Notes Recruitment at 1 centre in the USA.
Study finished prior to achieving target sample size due to recall of Vapotherm units.
Study authors provided a full-text manuscript including results.
Vapotherm provided equipment for the study.
No information regarding conflicts of interest available.
Risk of bias
Random sequence genera- Unclear risk Stratified into 27–30 weeks' and 31–34 weeks' GA. Permuted block randomisa-
tion (selection bias) tion.
Allocation concealment Low risk Sealed envelopes.

(selection bias)

mance bias)
Blinding of outcome as- Unclear risk Standardised criteria for respiratory failure, though frequency of blood gases
sessment (detection bias) and recording of apnoea not blinded.
try
Blinding of outcome as- High risk Assessment of nasal injury non-blinded. Assessment method not stated.
Informed decisions.
Nair 2005 (Continued)

Nasal trauma
(attrition bias)
All outcomes
Selective reporting (re- Unclear risk Trial not registered.

porting bias)
Roberts 2016
Participants 564 preterm infants 28–36+6 weeks' GA with early respiratory distress
Interventions nHF (289 infants): initial gas flow 6–8 L/min, either Fisher & Paykel Optiflow Junior or Vapotherm Preci-
sion Flow
Nasal CPAP (285 infants): initial pressure 6–8 cmH2O, by ventilator, bubble or variable-flow
• Treatment failure within 72 hours, based on prespecified criteria:

◦ maximal support plus FiO2 ≥ 0.4
◦ pH ≤ 7.2 and pCO2 > 60 mmHg
◦ ≥ 2 episodes of apnoea requiring positive pressure ventilation within 24 hours or 6 episodes requir-
ing any intervention within 6 hours
◦ urgent need for intubation as determined by treating clinician
Secondary outcomes
• Mechanical ventilation within 72 hours

• Nasal trauma
• Other complications of prematurity
• Pneumothorax
• Death
• Cost of care
Notes Recruitment from 27 May 2013 to 16 June 2015 at 9 centres in Australia and Norway.
Funded by the Australian National Health and Medical Research Council.
1 study author declared potential of conflict of interest due to travel support from Fisher & Paykel. An-
other study author is an author on this Cochrane Review (BJM).
Cross-over to CPAP group allowed in event of nHF failure, prior to intubation. Surfactant not permitted
prior to intubation.
Risk of bias
Informed decisions.
Roberts 2016 (Continued)
Random sequence genera- Low risk Computer-generated randomisation sequence with variable block sizes.
Allocation concealment Low risk Sequentially numbered, sealed, opaque envelopes opened when eligibility
(selection bias) and consent criteria met.

mance bias)
Blinding of outcome as- Unclear risk Unblinded study, but objective treatment failure criteria. Reasons for treat-
sessment (detection bias) ment failure reported, and treatment failure reported separately to intubation.
try
Blinding of outcome as- Unclear risk Assessor unblinded to treatment arm but used validated scoring chart.
Nasal trauma

(attrition bias)
All outcomes
Selective reporting (re- Low risk Trial registered and protocol published.
porting bias)
Sharma 2019
Participants 100 infants 26–34+6 weeks' GA with mild–moderate respiratory distress within 6 hours of birth
Interventions nHF (50 infants): no information regarding device or flow rates
Nasal CPAP (50 infants): no information regarding device or pressure
Outcomes Primary outcomes
• Duration of non-invasive support

• Duration of oxygen supplementation
• Treatment failure (no criteria for definition)
Secondary outcomes

• Nasal trauma
• Air leak
• BPD
• PDA
Informed decisions.
Sharma 2019 (Continued)

• ROP
Notes Recruitment at 1 centre in India.
Paper stated study was double-blind but no information given regarding process of blinding. No infor-
mation regarding device, flow rate or pressure. Not intention-to-treat analysis (infants who required
mechanical ventilation excluded from analysis). Several secondary outcomes not reported. No trial reg-
istration.
Risk of bias
Random sequence genera- Low risk Computer-generated random numbers.

Allocation concealment High risk No information regarding allocation concealment.

(selection bias)
Blinding of participants Unclear risk Paper stated "double-blinded" but no information regarding this process.
mance bias)
Blinding of outcome as- High risk No objective criteria for intubation. Paper stated "double-blinded" but no in-
sessment (detection bias) formation regarding this process.
try
Blinding of outcome as- High risk Assessment method not stated.

Nasal trauma
Incomplete outcome data High risk Reason for missing outcome data likely to be related to true outcome, with
(attrition bias) either imbalance in numbers or reasons for missing data across intervention
All outcomes groups.
Selective reporting (re- High risk Trial not registered. No data reported for several secondary outcomes. Not in-
porting bias) tention-to-treat reporting of primary outcomes.
Shin 2017
Participants 87 preterm infants 30–35 weeks' GA aged < 24 hours with respiratory distress
Interventions nHF (42 infants): Fisher & Paykel Optiflow, initial flow rate 5 L/min, maximum 7 L/min
Nasal CPAP (43 infants): Infant Flow, initial pressure 5 cmH2O, maximum 7 cmH2O

Informed decisions.
Shin 2017 (Continued)

• Treatment failure (time point not defined), based on prespecified criteria of maximal support and:
◦ pH < 7.2 and PaCO2 > 65 mmHg
◦ FiO2 > 0.4
◦ apnoea (> 2–3 episodes/hour)
Secondary outcomes

• Air leak
• Nasal trauma
• Surfactant
• BPD (NIH consensus definition)
• Symptomatic PDA (requiring pharmacological or surgical treatment)
• IVH ≥ grade III
• PVL; sepsis (defined as bacteraemia)
• NEC ≥ stage 2 (modified Bell's)
• Days to full enteral feeds
Notes Recruitment from August 2010 to August 2013 at 1 centre in Korea.
No funding stated, no conflicts of interest disclosed.
20% non-inferiority margin.
Infants in nHF arm could receive CPAP in event of treatment failure; infants in CPAP arm could receive
BiPAP.
Risk of bias
Random sequence genera- Low risk Computer-generated random numbers.

Allocation concealment Low risk Sealed opaque envelopes, opened once consent/inclusion criteria met.
(selection bias)

mance bias)
Blinding of outcome as- Unclear risk Non-blinded study, but treatment failure prespecified (some subjectivity, e.g.
sessment (detection bias) range for apnoea).
try

Nasal trauma

(attrition bias)
All outcomes
Selective reporting (re- Unclear risk Not strictly intention-to-treat analysis (1 infant excluded from analysis due to
porting bias) later diagnosis with congenital heart disease, 1 due to wrong device applied).
Informed decisions.
Shin 2017 (Continued)
Wang 2018
Methods Randomised trial
Participants 89 preterm infants 28–32+6 weeks' GA and BW 1000–1500 g with respiratory distress
Interventions nHF (43 infants): Fisher & Paykel Optiflow Junior, initial flow rate 5 L/min
Nasal intermittent positive pressure ventilation (46 infants): SLE5000 Ventilator, initial PIP 18
cmH2O, PEEP 6 cmH2O, rate 40 breaths/min
• Treatment failure (endotracheal intubation and surfactant administration) within 72 hours, based on
prespecified criteria:
◦ pH < 7.2 and PaCO2 > 60 mmHg
◦ PaO2 < 50 mmHg
◦ FiO2 > 0.4
◦ NEC
◦ apnoea (> 6 episodes in 6 hours, ≥ 2 episodes requiring PPV)
Secondary outcomes
• Surfactant therapy
• Pneumonia
• Duration of invasive ventilation
• Duration of non-invasive ventilation
• BPD
• Moderate-to-severe BPD
• NEC ≥ Stage IIB
• ROP
• Grade III–IV IVH
• PDA
• Nasal injury
• Air leak
Notes Recruitment at 1 centre in China.
No funding stated, no information regarding conflicts of interest available.
Full text in Chinese, translated to English by Dr Wei Qi Fan.
No cross-over or 'rescue' CPAP use. No surfactant permitted prior to intubation. No information on

consent or age at randomisation. No sample size calculation or information regarding randomisation
process. Infants excluded from analysis if 'discharged and failed to complete treatment.'
Risk of bias
Informed decisions.
Wang 2018 (Continued)
Random sequence genera- High risk No information on randomisation process.

Allocation concealment High risk No information on allocation concealment.

(selection bias)

mance bias)
Blinding of outcome as- Unclear risk Unblinded study. Prespecified treatment failure criteria, but some subjectivity
sessment (detection bias) (e.g. duration of FiO2 increase).
try

Nasal trauma

(attrition bias)
All outcomes
Selective reporting (re- High risk Unclear whether trial registered. Infants excluded from analysis if discharged.
porting bias)
Yoder 2013
Methods Multicentre randomised controlled trial
Participants 432 preterm infants > 28 weeks' GA and BW > 1000 g being managed with non-invasive respiratory sup-
port either as primary support after birth, or postextubation in 7 centres in the USA and China.
Interventions HFNC (58 preterm infants): various devices starting at 3–5 L/min, increased as required to maximum of
3 L/min above starting point
Nasal CPAP (67 preterm infants): 5–6 cmH2O or equivalent to end expiratory pressure on ventilator,
subsequently increased to maximum 8 cmH2O
Outcomes • Need for intubation within 72 hours of treatment assignment

• Delayed intubation
• Significant apnoea
• Pulmonary air leaks
• Feed intolerance
• Abdominal distension
• NEC
• Intestinal perforation
• Late-onset nosocomial infection
Informed decisions.
Yoder 2013 (Continued)

• Nasal mucosal injury
• Infant comfort
• BPD (based on need for oxygen as assessed by an oxygen reduction test at 36 weeks' PMA)
• Death
• Oxygen requirement at discharge
Notes Recruitment from December 2007 to April 2012 at multiple centres in the USA and China.
Study underpowered because lower incidence than expected of intubation in infants treated with
CPAP.
No cross-over permitted between interventions in the first 72 hours of the study.
More infants in the HFNC group crossed over to the alternative treatment after 72 hours.
6 Vapotherm devices were provided for use at 3 study sites.
No conflicts of interest declared.
Risk of bias
Random sequence genera- Low risk Random number generation.

Allocation concealment Low risk Opaque sealed envelopes.

(selection bias)

mance bias)
Blinding of outcome as- Unclear risk Unblinded study but prespecified criteria for intubation.
try
Blinding of outcome as- High risk Subjective assessment, non-blinded, criteria not stated.
Nasal trauma

(attrition bias)
All outcomes
Selective reporting (re- Unclear risk Some outcomes not reported in detail. Feeding intolerance not reported.
porting bias)
BiPAP: bilevel positive airway pressure; BPD: bronchopulmonary dysplasia; BW: birth weight; CLD: chronic lung disease; CPAP: continuous
positive airway pressure; CXR: chest x-ray; FiO2: fraction of inspired oxygen; g: gram; GA: gestational age; HF: high flow; HFNC: high flow
nasal cannula; INSURE: INtubation, SURfactant, Extubation; IVH: intraventricular haemorrhage; NEC: necrotising enterocolitis; nHF: nasal
high flow; NICU: neonatal intensive care unit; NIH: National Institutes of Health; NIMV: nasal intermittent mandatory ventilation; NIPPV:
nasal intermittent positive pressure ventilation; PaCO2: partial pressure of carbon dioxide in arterial blood; pCO2: partial pressure of carbon
Informed decisions.
dioxide; PDA: patent ductus arteriosus; PEEP: positive end expiratory pressure; PIP: peak inspiratory pressure; PMA: postmenstrual age;
PVL: periventricular leukomalacia; RDS: respiratory distress syndrome; ROP: retinopathy of prematurity; SiPAP: synchronised inspiratory
positive airway pressure; SpO2: oxygen saturation.
Characteristics of excluded studies [ordered by study ID]
Study Reason for exclusion
Akbarian-Rad 2020 This RCT compared nHF with CPAP following surfactant administration via INSURE (not as primary
respiratory support). This study did not examine the use of nHF for the target indication for this re-
view.
Boumecid 2007 This cross-over trial compared variable flow CPAP with constant-flow CPAP and non-humidified
nasal cannula at 2 L/min. No outcomes of relevance to this review were recorded.
Campbell 2006 This was a single-centre study that randomised 40 intubated preterm infants to humidified, un-
heated nHF (mean gas flow 1.6 L/min) or variable flow CPAP (5–6 cmH2O) after extubation. This
study did not examine the use of nHF for the target indication for this review.
Capasso 2005 This study did not examine the use of nasal cannula for the target indication for this review; resus-
citation at birth was studied.
Charki 2020 This was a non-randomised study of nHF versus nasal CPAP in preterm infants following extuba-
tion.
Chen 2015 This was an RCT of 66 very low birth weight infants assigned to nHF or nasal CPAP following surfac-
tant therapy. This study did not examine the use of nHF for the target indication for this review.
Chen 2020 This study randomised 94 ELBW infants to nHF or CPAP following extubation within the first 7 days
of life. This study did not examine the use of nHF for the target indication for this review.
Collins 2013b This RCT allocated 132 intubated preterm infants < 32 weeks to nHF or CPAP upon extubation. This
Courtney 2001 This cross-over trial compared variable flow CPAP with constant flow CPAP, and a modified nasal
cannula attached to a constant flow CPAP circuit. No outcomes of relevance to this review were
recorded.
de Jongh 2014 This study was non-randomised. It compared work of breathing on CPAP compared with nHF. Ini-
tial modality was dependent on what infant was already receiving. No outcomes of relevance to
this review were recorded.
Elkhwad 2014 This RCT presented in abstract form allocated ELBW infants to nHF or CPAP following extubation.
This study did not examine the use of nHF for the target indication for this review.
Hua 2013 This RCT presented in abstract form randomised infants to nHF or CPAP at day 5 of life. The study
did not examine the use of HF for the target indication for this review.
Iranpour 2011 This RCT, published in Persian, that enrolled 70 preterm infants at 24 hours of age following surfac-
tant administration. This study did not examine the use of nHF for the target indication for this re-
view.
Kadivar 2016 This RCT allocated 54 patients to nHF or CPAP following INSURE. This study did not examine the
use of nHF for the target indication for this review.
Kang 2016 This RCT allocated infants to nHF or CPAP following 'ventilator weaning'. This study did not exam-
ine the use of nHF for the target indication for this review.
Informed decisions.
Study Reason for exclusion
Klingenberg 2014 In this RCT, patient comfort was compared between nHF and CPAP. No outcomes of relevance to
this review were recorded.
Lampland 2009 This non-randomised cross-over study compared CPAP with nHF. No outcomes of relevance to this
review were recorded.
Lee 2011 This study presented in abstract form examined nHF versus nasal CPAP following extubation in
preterm infants. This study did not examine the use of nHF for the target indication for this review.
Liu 2014 This RCT allocated 255 intubated newborn infants < 7 days of life to nHF or CPAP upon extubation.
Ma 2014 This study examined the use of nHF following extubation. This study did not examine the use of
nHF for the target indication for this review.
Manley 2013 This was a non-inferiority RCT that enrolled very preterm infants to nHF or CPAP after extubation.
Miller 2010 This was a pilot RCT that enrolled preterm infants to 1 of 2 brands of nHF following extubation. This
Mostafa-Gharehbaghi 2015 This RCT allocated infants to nHF or CPAP following surfactant provision via INSURE. This study did
not examine the use of nHF for the target indication for this review.
Nasef 2015 Preterm infants < 1500 g were randomised in a cross-over design to receive 2 hours of either infant
flow CPAP (IF-CPAP) at 5–6 cmH2O or nHF with the flow rate adjusted to achieve an equivalent pha-
ryngeal pressure. No outcomes of relevance to this review were recorded.
Pyon 2008 This cross-over trial compared nasal CPAP with nHF. No outcomes of relevance to this review were
recorded.
Saslow 2006 This cross-over trial compared CPAP with nHF. No outcomes of relevance to this review were
recorded.
Shokouhi 2019 This RCT allocated infants to nHF or CPAP following surfactant provision via INSURE. This study did
not examine the use of nHF for the target indication for this review.
Soonsawad 2016 This RCT allocated infants to nHF, or continuing CPAP, for weaning off CPAP. This study did not ex-
amine the use of nHF for the target indication for this review.
Soonsawad 2017 This RCT allocated infants to nHF or CPAP following extubation. This study did not examine the use
of nHF for the target indication for this review.
Sreenan 2001 This cross-over trial of CPAP and non-humidified nHF was non-randomised.
Wilson 1996 This study examined nasal cannula compared with nasopharyngeal catheters at flow rates < 1 L/
min.
Woodhead 2006 This RCT allocated infants to nHF or CPAP following extubation. This study did not examine the use
of nHF for the target indication for this review
Zivanovic 2019 This was a retrospective observational study (non-randomised).
CPAP: continuous positive airway pressure; ELBW: extremely low birth weight; HF: high flow; IF-CPAP: infant flow CPAP; INSURE: INtubation,
SURfactant, Extubation; nHF: nasal high flow; RCT: randomised controlled trial.
Informed decisions.
Characteristics of studies awaiting classification [ordered by study ID]
Awad 2021
Methods RCT
Participants Preterm infants < 35 weeks' gestation
Interventions nHF
CPAP
• Treatment failure
Secondary outcomes
• Mortality
• Sepsis
• NEC
• IVH
• BPD
Notes
Balasubramanian 2022
Methods Single-centre, double-blind, RCT
Participants Preterm infants ≥ 28 weeks' gestation
Interventions Increased nasal flow therapy (8–10 L/min)
Standard nasal flow therapy (5–7 L/min)
Outcomes • Need for higher respiratory support (CPAP or mechanical ventilation) or surfactant therapy
Notes
Cetinkaya 2018
Methods RCT
Participants Preterm infants
Interventions nHF
CPAP
NIPPV
• Intubation
Informed decisions.
Cetinkaya 2018 (Continued)

Secondary outcomes

• Duration of oxygen
• BPD
• Air leak
• ROP
• IVH
Notes Attempted to contact authors for further information but received no response.
Febre 2015
Methods RCT
Participants 20 preterm and term infants BW 400–5000 g, needing FiO2 > 30%
Interventions HFNC (quote) "Adaptive Dynamic Inspiratory Nasal Apparatus;" 2–4 L/min, pop-off valve if circuit
pressure exceeds 10 cmH2O
CPAP Hudson prongs 4–8 cmH2O
Outcomes • Oxygen requirement

• Level of pressure or flow support
• Radiological changes
• Blood gas measurement
• Time to wean off protocol, and failure to wean or necessity for endotracheal intubation
Notes Potential for allocation bias
Iskandar 2019
Methods RCT
Participants Preterm infants 28–35 weeks' gestation
Interventions nHF
CPAP
Outcomes • Treatment failure

• Length of device use
• Length of Kangaroo Mother Care
• Full enteral feeding time
• Pain score
• Nasal trauma
• Systemic complications
Notes
Informed decisions.
Lawrence 2012
Methods RCT
Participants Infants 26 and 33 6/7 weeks' GA and BW 750–2500 g
Interventions Nasal CPAP
HFNC
Outcomes • Transpleural pressure

• PDA
• NEC
• IVH
• Air leaks
Notes
Oktem 2021
Methods RCT
Participants Preterm infants < 32 weeks' gestation
Interventions nHF
CPAP
NIPPV
Nasal high-frequency oscillatory ventilation
• Intubation requirement
Secondary outcomes
• Duration of non-invasive ventilation

• Air leak syndrome
• IVH
• NEC
• Nasal injury
• Increased secretions
• Agitation
• Mortality
Notes
Park 2011
Methods No information available
Informed decisions.
Park 2011 (Continued)
Participants No information available
Interventions No information available
Outcomes No information available
Notes Abstract submitted to Pediatric Academic Societies conference: no further information available.
Shirvani 2019
Methods RCT
Participants 60 infants with RDS < 34 weeks' GA and BW < 2000 g
Interventions nHF
CPAP
Outcomes • Duration of hospitalisation

• Day to full feeds
Notes No raw data provided for primary outcomes of interest of review (odds ratios only). No further in-
formation available from study authors.
BPD: bronchopulmonary dysplasia; BW: birth weight; CPAP: continuous positive airway pressure; FiO2; fraction of inspired oxygen; GA:
gestational age; HF: high flow; HFNC: high flow nasal cannula; IVH: intraventricular haemorrhage; NEC: necrotising enterocolitis; nHF: nasal
high flow; NIPPV: nasal intermittent positive pressure ventilation; PDA: patent ductus arteriosus; RCT: randomised controlled trial; RDS:
respiratory distress syndrome; ROP: retinopathy of prematurity.
Characteristics of ongoing studies [ordered by study ID]
ACTRN12610000677000
Study name High flow support versus continuous positive airway pressure (CPAP) support in non-acute respira-
tory support for preterm infants from 30 weeks' corrected gestation
Methods RCT
30 infants
Participants Infants aged ≥ 5 days, ≥ 30 weeks' corrected GA, < 32 weeks' corrected GA, on CPAP in < 5 cmH2O
and < 25% oxygen
Interventions HFNC (4–6 L/min)
Outcomes • CLD
• Stability of treatment
Starting date 31 August 2010
Contact information Ashley McEwan (ashley.mcewan@hotmail.com)
Notes ACTRN12610000677000
Informed decisions.
ACTRN12611000233921
Study name High-flow for infants in non-tertiary centres (HINT trial)
Methods RCT
Participants Infants > 32 weeks' gestation aged 1–24 hours
Interventions HF flow rate 6–7 L/min
Ambient (head box oxygen)
Outcomes • Treatment failure

• Transfer to tertiary centre
Starting date 3 March 2011
Contact information A/Prof Adam Buckmaster (abuckmaster@nsccahs.health.nsw.gov.au)
Notes
CTRI/2017/09/009910
Study name High flow nasal cannulae versus nasal continuous positive airway pressure in neonates with respi-
ratory distress syndrome
Methods Non-randomised prospective cohort study
Participants Infants < 36 weeks' GA
Interventions nHF (Fisher & Paykel Optiflow Junior). Flow rates 1–8 L/min
Nasal CPAP (Drager Babylog 8000). CPAP pressure 4–6 cmH2O
Outcomes • Mechanical ventilation within 72 hours of initiation of therapy

• Days of non-invasive support
• Days of oxygen supplementation
• Nasal injury
• Pneumothorax
Starting date 9 February 2015
Contact information Dr Leslie Lewis (leslielewis1@gmail.com)
Notes Not prospectively registered
CTRI/2019/10/021633
Study name Breathing stabilization in small babies at the time of birth
Methods RCT
Informed decisions.
CTRI/2019/10/021633 (Continued)
124 infants
Participants Infants 28–36+6 weeks' GA and BW ≥ 800 g with respiratory distress and FiO2 > 0.3
Interventions Infants randomised to 1 of 2 groups for delivery room stabilisation
nHF (starting flow 4–6 L/min, maximum 8 L/min)
Nasal CPAP (starting pressure 5 cmH2O, maximum pressure 8 cmH2O)
Secondary outcomes
• Time to treatment failure

• Need for surfactant
• Duration of respiratory support and supplemental oxygen
• Age of starting feeds and time to achieve full feeds
• Duration of hospital stay
• Weight at discharge
• Adverse events
Starting date 23 October 2019
Contact information Sripana Basu (sriparna.neonat@aiimsrishikesh.edu.in)
Notes
Irct2016052510026N
Study name Therapeutic effect of heated, humidified, high-flow nasal cannula (HHHFNC) in respiratory distress
syndrome
Methods Trial design not stated
Participants Premature infants < 1500 g with RDS
Interventions NIMV: PIP 16–20 cmH2O, PEEP 5–6 cmH2O, rate 40–50 breaths/min, inspiratory time 0.4 seconds
and flow rate 8–10 L/min
High flow: 2.5–3 L/min
Surfactant if FiO2 > 0.3 via INSURE
Outcomes • Duration of non-invasive respiratory support
Starting date Not stated
Contact information Not stated
Notes
Informed decisions.
Irct20180226038865N
Study name Comparison of two forms of non-invasive respiratory supporting preterm infants
Methods Trial design not stated
Participants Preterm infants with RDS requiring surfactant
Interventions Nasal CPAP
Humidified HFNC
Outcomes • Response to treatment
Starting date Not stated
Contact information Not stated
Notes
Irct20190623043988N
Study name Continuous positive airway pressure or high flow nasal cannula for respiratory distress syn-
drome
Methods RCT
Participants Preterm infants BW < 2000 g and < 34 weeks' gestation
Interventions nHF 2–5 L/min
CPAP 4–6 cmH2O
Outcomes • Intervention 'effectiveness'
Starting date
Contact information
Notes
Irct20200616047788N
Study name Comparing two respiratory support methods in RDS treatment of premature neonates
Methods RCT
Participants Preterm infants 28–34 weeks' gestation
Interventions nHF
CPAP
Informed decisions.
Irct20200616047788N (Continued)
• RDS score
Secondary outcomes
• Air leak syndromes

• BPD
• IVH
• Intubation
• PDA
Starting date
Contact information
Notes
ISRCTN66716753
Study name Can high flow nasal prongs therapy facilitate earlier establishment of full oral feeds in babies who
are nasal continuous positive airway pressure dependent at 32 weeks gestation?
Methods RCT
44 infants
Participants Infants aged < 30 weeks and BW < 1500 g requiring CPAP at 32 weeks' corrected age with oxygen re-
quirement < 30%
Interventions Continue on nasal CPAP
HF nasal prongs 7 L/min
Outcomes • Establishment of full oral feeding
Starting date February 2013
Contact information Dr Jan Miletin (jmiletin@coombe.ie)
Notes ISRCTN66716753
NCT01270581
Study name High flow nasal cannula vs bubble nasal CPAP for the treatment of transient tachypnoea of the
newborn in infants > 35 weeks gestation
Methods RCT
Estimated enrolment 66 infants
Participants Infants > 35 weeks' gestation diagnosed with transient tachypnoea and admitted to NICU within
first 24 hours of life
Interventions HFNC
Informed decisions.
NCT01270581 (Continued)
Bubble nasal CPAP
Outcomes • Duration of respiratory support
Starting date July 2010
Contact information Andrea Weintraub, Mount Sinai School of Medicine, New York (andrea.weintraub@mssm.edu)
Notes ClinicalTrials.gov identifier: NCT01270581
NCT02055339
Study name Comparison of nasal continuous positive airway pressure with low flow oxygen versus heated, hu-
midified high flow nasal cannula for oral feeding of the premature infant (CHOMP Trial): a pilot
study
Methods RCT
Sample size 40 infants
Participants Preterm infants born < 28 weeks' gestation who were then 34 weeks' corrected GA, dependent on
non-invasive respiratory support, and receiving nasogastric feeds.
Interventions HFNC (Fisher & Paykel)
Infant flow CPAP
Outcomes • Time to reach full oral feeds
Contact information Sandra Leibel, Mount Sinai Hospital, New York (sleibel@mtsinai.on.ca)
Notes ClinicalTrials.gov Identifier: NCT02055339
NCT02499744
Study name Humidified high flow nasal cannula versus nasal intermittent positive ventilation in neonates as
primary respiratory support: a randomised controlled trial
Methods Randomised trial
Participants Preterm infants > 28 weeks' GA and BW > 1000 g with respiratory distress
Interventions High flow (2–8 L/min)
NIPPV (12–22 cmH2O/5–7 cmH2O)
Outcomes • Endotracheal intubation within 72 hours
Contact information Gao WeiWei
Informed decisions.
NCT02499744 (Continued)
Notes
UMIN000018983
Study name Effective and safe use of heated humified high flow nasal cannula in neonates
Methods RCT
Participants Infants > 28 weeks' GA and BW > 1000 g with neonatal 'respiratory disorder' not responsive to initial
nasal CPAP therapy
Interventions Nasal CPAP (no details given)
nHF (no details given)
Outcomes • Improvement in respiratory acidosis and hypercapnia 1 hour after intervention

• Improvement in oxygenation 1 hour after intervention
Starting date 1 November 2015
Contact information Atsuko Taki (ataki.ped@tmd.ac.jp)
Notes Planned recruitment of 20 infants
BPD: bronchopulmonary dysplasia; BW: birth weight; CLD: chronic lung disease; CPAP: continuous positive airway pressure; FiO2: fraction
of inspired oxygen; g: gram; GA: gestational age; HF: high flow; HFNC: high-flow nasal cannula; INSURE: INtubation, SURfactant, Extubation;
IVH: intraventricular haemorrhage; nHF: nasal high flow; NICU: neonatal intensive care unit; nasal intermittent mandatory ventilation;
NIPPV: nasal intermittent positive pressure ventilation; PDA: patent ductus arteriosus; PEEP: positive end expiratory pressure; PIP: peak
inspiratory pressure; RCT: randomised controlled trial; RDS: respiratory distress syndrome.
DATA AND ANALYSES
Comparison 1. Nasal high flow (nHF) compared with continuous positive airway pressure (CPAP) for primary
respiratory support in preterm infants
Outcome or subgroup title No. of studies No. of partici- Statistical method Effect size
pants
1.1 Death or bronchopulmonary 7 1830 Risk Ratio (M-H, Fixed, 95% CI) 1.09 [0.74, 1.60]
dysplasia
1.1.1 28–32 weeks 5 567 Risk Ratio (M-H, Fixed, 95% CI) 1.17 [0.72, 1.89]
1.1.2 ≥ 32 weeks 5 1089 Risk Ratio (M-H, Fixed, 95% CI) 1.48 [0.58, 3.80]
1.1.3 < 37 weeks (subgroup data 2 174 Risk Ratio (M-H, Fixed, 95% CI) 0.61 [0.24, 1.53]
not available)
1.2 Death 9 2009 Risk Ratio (M-H, Fixed, 95% CI) 0.78 [0.44, 1.39]
Informed decisions.
pants
1.2.3 < 37 weeks' (subgroup data 4 353 Risk Ratio (M-H, Fixed, 95% CI) 0.57 [0.28, 1.16]
not available)
1.3 Bronchopulmonary dysplasia 8 1917 Risk Ratio (M-H, Fixed, 95% CI) 1.14 [0.74, 1.76]
not available)
1.4 Treatment failure within 72 9 2042 Risk Ratio (M-H, Fixed, 95% CI) 1.70 [1.41, 2.06]
hours of trial entry
not available)
1.5 Mechanical ventilation within 9 2042 Risk Ratio (M-H, Fixed, 95% CI) 1.04 [0.82, 1.31]
72 hours of trial entry
not available)
1.6 Mechanical ventilation at any 4 1175 Risk Ratio (M-H, Fixed, 95% CI) 1.19 [0.92, 1.55]
time point after trial entry
1.7 Duration of any respiratory 7 1808 Mean Difference (IV, Fixed, 95% 0.52 [0.25, 0.80]
support (days) CI)
1.8 Duration of supplemental oxy- 6 1723 Mean Difference (IV, Fixed, 95% -0.07 [-0.20, 0.05]
gen (days) CI)
1.9 Surfactant treatment 8 1590 Risk Ratio (M-H, Fixed, 95% CI) 0.99 [0.87, 1.13]
1.10 Duration of hospitalisation 7 1808 Mean Difference (IV, Fixed, 95% -0.16 [-1.54, 1.21]
(days) CI)
1.11 Pneumothorax 10 2094 Risk Ratio (M-H, Fixed, 95% CI) 0.66 [0.40, 1.08]
1.12 Nasal trauma 7 1595 Risk Ratio (M-H, Fixed, 95% CI) 0.49 [0.36, 0.68]
1.13 Nosocomial sepsis 9 2022 Risk Difference (M-H, Fixed, -0.01 [-0.03, 0.01]
95% CI)
Informed decisions.
pants
1.14 Gastrointestinal perforation 6 1469 Risk Difference (M-H, Fixed, 0.00 [-0.01, 0.01]
or severe necrotising enterocolitis 95% CI)
1.15 Time to full feeds (days) 6 1741 Mean Difference (IV, Fixed, 95% -0.27 [-0.76, 0.22]
CI)
1.16 Retinopathy of prematurity 4 1259 Risk Difference (M-H, Fixed, 0.00 [-0.01, 0.01]
95% CI)
1.17 Subgroup analysis – mechani- 8 1942 Risk Ratio (M-H, Fixed, 95% CI) 1.02 [0.81, 1.30]
cal ventilation with or without sur-
factant permitted
1.17.1 Surfactant permitted 5 874 Risk Ratio (M-H, Fixed, 95% CI) 0.86 [0.61, 1.21]
1.17.2 Surfactant not permitted 3 1068 Risk Ratio (M-H, Fixed, 95% CI) 1.19 [0.86, 1.66]
1.18 Subgroup analysis – pneu- 10 2094 Risk Ratio (M-H, Fixed, 95% CI) 0.66 [0.40, 1.08]
mothorax with or without surfac-
tant permitted
1.18.1 Surfactant not permitted 5 1220 Risk Ratio (M-H, Fixed, 95% CI) 0.48 [0.23, 1.00]
1.18.2 Surfactant permitted 5 874 Risk Ratio (M-H, Fixed, 95% CI) 0.89 [0.45, 1.76]
1.19 Subgroup analysis – mechani- 9 2042 Risk Ratio (M-H, Fixed, 95% CI) 1.01 [0.80, 1.28]
cal ventilation with or without sec-
ond-line CPAP permitted
1.19.1 Rescue CPAP permitted 3 1215 Risk Ratio (M-H, Fixed, 95% CI) 1.17 [0.85, 1.63]
1.19.2 Rescue CPAP not permitted 6 827 Risk Ratio (M-H, Fixed, 95% CI) 0.86 [0.62, 1.20]
Informed decisions.
Analysis 1.1. Comparison 1: Nasal high flow (nHF) compared with continuous positive airway pressure
(CPAP) for primary respiratory support in preterm infants, Outcome 1: Death or bronchopulmonary dysplasia
nHF CPAP Risk Ratio Risk Ratio

Study or Subgroup Events Total Events Total Weight M-H, Fixed, 95% CI M-H, Fixed, 95% CI
1.1.1 28–32 weeks

Yoder 2013 3 20 1 17 2.4% 2.55 [0.29 , 22.31]
Roberts 2016 18 140 18 149 39.0% 1.06 [0.58 , 1.96]
Lavizzari 2016 6 48 8 51 17.3% 0.80 [0.30 , 2.13]
Murki 2018 4 58 1 68 2.1% 4.69 [0.54 , 40.79]
Manley 2019 0 9 0 7 Not estimable
Subtotal (95% CI) 275 292 60.8% 1.17 [0.72 , 1.89]
Total events: 31 28
Heterogeneity: Chi² = 2.76, df = 3 (P = 0.43); I² = 0%
Test for overall effect: Z = 0.64 (P = 0.52)
1.1.2 ≥ 32 weeks
Yoder 2013 2 38 0 50 1.0% 6.54 [0.32 , 132.33]
Roberts 2016 2 138 3 137 6.7% 0.66 [0.11 , 3.90]
Lavizzari 2016 1 110 1 107 2.3% 0.97 [0.06 , 15.35]
Murki 2018 1 75 2 71 4.6% 0.47 [0.04 , 5.11]
Manley 2019 3 176 0 187 1.1% 7.44 [0.39 , 142.92]
Subtotal (95% CI) 537 552 15.6% 1.48 [0.58 , 3.80]
Total events: 9 6
1.1.3 < 37 weeks (subgroup data not available)

Nair 2005 0 33 1 34 3.3% 0.34 [0.01 , 8.13]
Farhat 2018 6 54 9 53 20.3% 0.65 [0.25 , 1.71]
Subtotal (95% CI) 87 87 23.6% 0.61 [0.24 , 1.53]
Total events: 6 10
Total (95% CI) 899 931 100.0% 1.09 [0.74 , 1.60]

Total events: 46 44
Heterogeneity: Chi² = 8.09, df = 10 (P = 0.62); I² = 0% 0.001 0.1 1 10 1000
Test for overall effect: Z = 0.43 (P = 0.67) Favours nHF Favours CPAP
Test for subgroup differences: Chi² = 2.03, df = 2 (P = 0.36), I² = 1.4%
Informed decisions.
Analysis 1.2. Comparison 1: Nasal high flow (nHF) compared with continuous positive
airway pressure (CPAP) for primary respiratory support in preterm infants, Outcome 2: Death

1.2.1 28–32 weeks

Yoder 2013 0 20 0 17 Not estimable
Roberts 2016 1 140 1 149 4.1% 1.06 [0.07 , 16.85]
Lavizzari 2016 0 48 1 51 6.2% 0.35 [0.01 , 8.48]
Murki 2018 3 58 1 68 3.9% 3.52 [0.38 , 32.90]
Subtotal (95% CI) 275 292 14.1% 1.43 [0.36 , 5.64]
Total events: 4 3
1.2.2 ≥ 32 weeks
Yoder 2013 0 38 0 50 Not estimable
Roberts 2016 0 138 0 137 Not estimable
Lavizzari 2016 0 110 0 107 Not estimable
Murki 2018 1 75 2 71 8.7% 0.47 [0.04 , 5.11]
Manley 2019 2 176 0 187 2.1% 5.31 [0.26 , 109.85]
Subtotal (95% CI) 537 552 10.7% 1.40 [0.29 , 6.85]
Total events: 3 2
1.2.3 < 37 weeks' (subgroup data not available)

Nair 2005 0 33 0 34 Not estimable
Farhat 2018 6 54 7 53 29.9% 0.84 [0.30 , 2.34]
Demirel 2019 0 53 0 54 Not estimable
Armanian 2019 4 35 11 37 45.2% 0.38 [0.13 , 1.10]
Subtotal (95% CI) 175 178 75.1% 0.57 [0.28 , 1.16]
Total events: 10 18
Total (95% CI) 987 1022 100.0% 0.78 [0.44 , 1.39]

Total events: 17 23
Informed decisions.
(CPAP) for primary respiratory support in preterm infants, Outcome 3: Bronchopulmonary dysplasia

1.3.1 28–32 weeks

Yoder 2013 3 20 1 17 3.2% 2.55 [0.29 , 22.31]
Roberts 2016 17 140 17 149 48.1% 1.06 [0.57 , 2.00]
Lavizzari 2016 6 48 7 51 19.8% 0.91 [0.33 , 2.52]
Murki 2018 1 58 0 68 1.3% 3.51 [0.15 , 84.51]
Subtotal (95% CI) 275 292 72.4% 1.13 [0.68 , 1.88]
Total events: 27 25
1.3.2 ≥ 32 weeks
Yoder 2013 2 38 0 50 1.3% 6.54 [0.32 , 132.33]
Roberts 2016 2 138 3 137 8.8% 0.66 [0.11 , 3.90]
Lavizzari 2016 1 110 1 107 3.0% 0.97 [0.06 , 15.35]
Murki 2018 0 75 0 71 Not estimable
Manley 2019 2 176 0 187 1.4% 5.31 [0.26 , 109.85]
Subtotal (95% CI) 537 552 14.4% 1.70 [0.57 , 5.04]
Total events: 7 4

Nair 2005 0 33 1 34 4.3% 0.34 [0.01 , 8.13]
Shin 2017 1 43 0 44 1.4% 3.07 [0.13 , 73.30]
Farhat 2018 0 54 2 53 7.4% 0.20 [0.01 , 4.00]
Subtotal (95% CI) 130 131 13.1% 0.56 [0.12 , 2.58]
Total events: 1 3
Total (95% CI) 942 975 100.0% 1.14 [0.74 , 1.76]

Total events: 35 32
Test for subgroup differences: Chi² = 1.34, df = 2 (P = 0.51), I² = 0%
Informed decisions.
Analysis 1.4. Comparison 1: Nasal high flow (nHF) compared with continuous positive airway pressure (CPAP)
for primary respiratory support in preterm infants, Outcome 4: Treatment failure within 72 hours of trial entry

1.4.1 28–32 weeks

Yoder 2013 0 20 2 17 2.0% 0.17 [0.01 , 3.34]
Roberts 2016 46 140 27 149 19.5% 1.81 [1.20 , 2.75]
Lavizzari 2016 9 48 5 51 3.6% 1.91 [0.69 , 5.30]
Murki 2018 20 58 5 68 3.4% 4.69 [1.88 , 11.71]
Manley 2019 5 9 1 7 0.8% 3.89 [0.58 , 26.17]
Subtotal (95% CI) 275 292 29.4% 2.11 [1.50 , 2.95]
Total events: 80 40
Test for overall effect: Z = 4.33 (P < 0.0001)
1.4.2 ≥ 32 weeks
Yoder 2013 6 38 7 50 4.5% 1.13 [0.41 , 3.08]
Roberts 2016 25 138 11 137 8.2% 2.26 [1.16 , 4.40]
Lavizzari 2016 8 110 10 107 7.6% 0.78 [0.32 , 1.90]
Murki 2018 15 75 6 71 4.6% 2.37 [0.97 , 5.76]
Manley 2019 44 176 21 187 15.2% 2.23 [1.38 , 3.59]
Subtotal (95% CI) 537 552 40.1% 1.85 [1.36 , 2.52]
Total events: 98 55
Test for overall effect: Z = 3.91 (P < 0.0001)

Farhat 2018 15 54 14 53 10.6% 1.05 [0.56 , 1.96]
Armanian 2019 19 35 13 37 9.4% 1.55 [0.91 , 2.63]
Demirel 2019 5 53 7 54 5.2% 0.73 [0.25 , 2.15]
Sharma 2019 6 50 7 50 5.2% 0.86 [0.31 , 2.37]
Subtotal (95% CI) 192 194 30.4% 1.12 [0.78 , 1.60]
Total events: 45 41
Total (95% CI) 1004 1038 100.0% 1.70 [1.41 , 2.06]

Total events: 223 136
Test for overall effect: Z = 5.46 (P < 0.00001) Favours nHF Favours CPAP
Informed decisions.
Analysis 1.5. Comparison 1: Nasal high flow (nHF) compared with continuous positive airway pressure (CPAP) for
primary respiratory support in preterm infants, Outcome 5: Mechanical ventilation within 72 hours of trial entry

1.5.1 28–32 weeks

Yoder 2013 0 20 2 17 2.2% 0.17 [0.01 , 3.34]
Lavizzari 2016 9 48 5 51 4.0% 1.91 [0.69 , 5.30]
Roberts 2016 30 140 24 149 19.3% 1.33 [0.82 , 2.16]
Murki 2018 5 58 5 68 3.8% 1.17 [0.36 , 3.85]
Manley 2019 3 9 1 7 0.9% 2.33 [0.30 , 17.88]
Subtotal (95% CI) 275 292 30.4% 1.33 [0.90 , 1.97]
Total events: 47 37
1.5.2 ≥ 32 weeks
Yoder 2013 6 38 7 50 5.0% 1.13 [0.41 , 3.08]
Lavizzari 2016 8 110 10 107 8.4% 0.78 [0.32 , 1.90]
Roberts 2016 13 138 9 137 7.5% 1.43 [0.63 , 3.24]
Murki 2018 3 75 6 71 5.1% 0.47 [0.12 , 1.82]
Manley 2019 14 176 13 187 10.5% 1.14 [0.55 , 2.37]
Subtotal (95% CI) 537 552 36.6% 1.02 [0.69 , 1.52]
Total events: 44 45

Farhat 2018 15 54 14 53 11.8% 1.05 [0.56 , 1.96]
Armanian 2019 5 35 12 37 9.7% 0.44 [0.17 , 1.12]
Demirel 2019 5 53 7 54 5.8% 0.73 [0.25 , 2.15]
Sharma 2019 6 50 7 50 5.8% 0.86 [0.31 , 2.37]
Subtotal (95% CI) 192 194 33.0% 0.78 [0.51 , 1.19]
Total events: 31 40
Total (95% CI) 1004 1038 100.0% 1.04 [0.82 , 1.31]

Informed decisions.
Analysis 1.6. Comparison 1: Nasal high flow (nHF) compared with continuous positive airway pressure (CPAP) for
primary respiratory support in preterm infants, Outcome 6: Mechanical ventilation at any time point after trial entry

Yoder 2013 9 58 9 67 10.1% 1.16 [0.49 , 2.71]

Roberts 2016 47 278 40 286 47.7% 1.21 [0.82 , 1.78]
Farhat 2018 21 54 20 53 24.4% 1.03 [0.64 , 1.67]
Manley 2019 20 185 15 194 17.7% 1.40 [0.74 , 2.65]
Total (95% CI) 575 600 100.0% 1.19 [0.92 , 1.55]

Total events: 97 84
Test for subgroup differences: Not applicable
for primary respiratory support in preterm infants, Outcome 7: Duration of any respiratory support (days)
nHF CPAP Mean Difference Mean Difference

Study or Subgroup Mean SD Total Mean SD Total Weight IV, Fixed, 95% CI IV, Fixed, 95% CI
Nair 2005 2.7 2.3 33 2.1 1.6 34 8.3% 0.60 [-0.35 , 1.55]
Yoder 2013 8.3 8.7 58 4.6 5.3 67 1.1% 3.70 [1.13 , 6.27]
Lavizzari 2016 4 3 158 3.5 3.7 158 13.7% 0.50 [-0.24 , 1.24]
Roberts 2016 4 3.7 278 3 3 286 24.3% 1.00 [0.44 , 1.56]
Shin 2017 2.8 2.1 42 2.2 1.7 43 11.4% 0.60 [-0.21 , 1.41]
Murki 2018 2.7 4.2 133 2.9 4 139 7.9% -0.20 [-1.18 , 0.78]
Manley 2019 1.9 2 185 1.7 2.7 194 33.2% 0.20 [-0.28 , 0.68]
Total (95% CI) 887 921 100.0% 0.52 [0.25 , 0.80]

Test for overall effect: Z = 3.73 (P = 0.0002) -10 -5 0 5 10
Test for subgroup differences: Not applicable Favours nHF Favours CPAP
for primary respiratory support in preterm infants, Outcome 8: Duration of supplemental oxygen (days)

Nair 2005 0.8 0.7 33 1.3 0.6 34 16.4% -0.50 [-0.81 , -0.19]
Yoder 2013 13.4 13.9 58 9.7 10.4 67 0.1% 3.70 [-0.66 , 8.06]
Lavizzari 2016 0 0.7 158 0 0.6 158 77.6% 0.00 [-0.14 , 0.14]
Roberts 2016 2 3.7 278 2 4.4 286 3.6% 0.00 [-0.67 , 0.67]
Murki 2018 4.1 6.7 133 4.6 5.9 139 0.7% -0.50 [-2.00 , 1.00]
Manley 2019 1.7 6.1 185 1.2 3.5 194 1.6% 0.50 [-0.51 , 1.51]
Total (95% CI) 845 878 100.0% -0.07 [-0.20 , 0.05]

Informed decisions.
Analysis 1.9. Comparison 1: Nasal high flow (nHF) compared with continuous positive airway
pressure (CPAP) for primary respiratory support in preterm infants, Outcome 9: Surfactant treatment

Nair 2005 10 33 11 34 4.1% 0.94 [0.46 , 1.90]

Lavizzari 2016 70 158 73 158 27.8% 0.96 [0.75 , 1.22]
Roberts 2016 40 278 30 286 11.3% 1.37 [0.88 , 2.14]
Shin 2017 12 42 7 43 2.6% 1.76 [0.77 , 4.02]
Farhat 2018 26 54 26 53 10.0% 0.98 [0.66 , 1.45]
Murki 2018 58 133 68 139 25.4% 0.89 [0.69 , 1.15]
Armanian 2019 22 35 26 37 9.6% 0.89 [0.64 , 1.24]
Demirel 2019 18 53 24 54 9.1% 0.76 [0.47 , 1.23]
Total (95% CI) 786 804 100.0% 0.99 [0.87 , 1.13]

(CPAP) for primary respiratory support in preterm infants, Outcome 10: Duration of hospitalisation (days)

Nair 2005 28 13 33 31 14 34 4.5% -3.00 [-9.47 , 3.47]

Yoder 2013 29.2 17.1 58 27.1 15.9 67 5.6% 2.10 [-3.72 , 7.92]
Lavizzari 2016 20 17.8 158 23 17.8 158 12.3% -3.00 [-6.93 , 0.93]
Roberts 2016 37 20 278 38 20.7 286 16.8% -1.00 [-4.36 , 2.36]
Shin 2017 20 9.3 42 21 11.9 43 9.2% -1.00 [-5.53 , 3.53]
Murki 2018 18 13 133 17 14 139 18.4% 1.00 [-2.21 , 4.21]
Manley 2019 18.9 11.4 185 18 12.3 194 33.2% 0.90 [-1.49 , 3.29]
Total (95% CI) 887 921 100.0% -0.16 [-1.54 , 1.21]

Informed decisions.
pressure (CPAP) for primary respiratory support in preterm infants, Outcome 11: Pneumothorax

Nair 2005 0 33 2 34 6.5% 0.21 [0.01 , 4.13]

Yoder 2013 0 58 3 67 8.6% 0.16 [0.01 , 3.12]
Lavizzari 2016 3 158 4 158 10.6% 0.75 [0.17 , 3.30]
Roberts 2016 0 278 6 286 17.0% 0.08 [0.00 , 1.40]
Shin 2017 2 42 0 43 1.3% 5.12 [0.25 , 103.50]
Farhat 2018 7 54 5 53 13.4% 1.37 [0.47 , 4.06]
Murki 2018 0 133 1 139 3.9% 0.35 [0.01 , 8.47]
Demirel 2019 2 53 1 54 2.6% 2.04 [0.19 , 21.81]
Armanian 2019 2 35 5 37 12.9% 0.42 [0.09 , 2.04]
Manley 2019 6 185 9 194 23.3% 0.70 [0.25 , 1.93]
Total (95% CI) 1029 1065 100.0% 0.66 [0.40 , 1.08]

Total events: 22 36
pressure (CPAP) for primary respiratory support in preterm infants, Outcome 12: Nasal trauma

Nair 2005 0 33 3 34 3.4% 0.15 [0.01 , 2.74]

Yoder 2013 12 57 15 64 14.1% 0.90 [0.46 , 1.76]
Roberts 2016 23 278 53 286 52.0% 0.45 [0.28 , 0.71]
Shin 2017 0 42 0 43 Not estimable
Farhat 2018 5 54 13 53 13.1% 0.38 [0.14 , 0.99]
Murki 2018 7 133 13 139 12.6% 0.56 [0.23 , 1.37]
Manley 2019 1 185 5 194 4.9% 0.21 [0.02 , 1.78]
Total (95% CI) 782 813 100.0% 0.49 [0.36 , 0.68]

Test for overall effect: Z = 4.33 (P < 0.0001) Favours nHF Favours CPAP
Informed decisions.
pressure (CPAP) for primary respiratory support in preterm infants, Outcome 13: Nosocomial sepsis
nHF CPAP Risk Difference Risk Difference

Nair 2005 1 33 1 34 3.3% 0.00 [-0.08 , 0.08]

Yoder 2013 3 58 2 67 6.2% 0.02 [-0.05 , 0.09]
Lavizzari 2016 10 158 13 158 15.6% -0.02 [-0.08 , 0.04]
Roberts 2016 7 278 13 286 27.9% -0.02 [-0.05 , 0.01]
Shin 2017 0 42 0 43 4.2% 0.00 [-0.04 , 0.04]
Farhat 2018 3 54 6 53 5.3% -0.06 [-0.16 , 0.05]
Murki 2018 13 133 13 139 13.5% 0.00 [-0.07 , 0.07]
Manley 2019 3 185 1 194 18.7% 0.01 [-0.01 , 0.03]
Demirel 2019 6 53 7 54 5.3% -0.02 [-0.14 , 0.11]
Total (95% CI) 994 1028 100.0% -0.01 [-0.03 , 0.01]

Total events: 46 56
Heterogeneity: Chi² = 6.01, df = 8 (P = 0.65); I² = 0% -0.2 -0.1 0 0.1 0.2
Analysis 1.14. Comparison 1: Nasal high flow (nHF) compared with continuous
positive airway pressure (CPAP) for primary respiratory support in preterm infants,
Outcome 14: Gastrointestinal perforation or severe necrotising enterocolitis

Yoder 2013 1 58 0 67 8.5% 0.02 [-0.03 , 0.06]

Lavizzari 2016 1 158 2 158 21.5% -0.01 [-0.03 , 0.02]
Roberts 2016 2 278 1 286 38.4% 0.00 [-0.01 , 0.02]
Shin 2017 0 42 0 43 5.8% 0.00 [-0.04 , 0.04]
Murki 2018 2 133 0 139 18.5% 0.02 [-0.01 , 0.04]
Demirel 2019 1 53 1 54 7.3% 0.00 [-0.05 , 0.05]
Total (95% CI) 722 747 100.0% 0.00 [-0.01 , 0.01]

Total events: 7 4
Informed decisions.
(CPAP) for primary respiratory support in preterm infants, Outcome 15: Time to full feeds (days)

Yoder 2013 22.5 17.7 58 18.8 12.4 67 0.8% 3.70 [-1.74 , 9.14]
Lavizzari 2016 9 6.7 158 10 7.4 158 9.8% -1.00 [-2.56 , 0.56]
Roberts 2016 32 18.5 278 32 20.7 286 2.3% 0.00 [-3.24 , 3.24]
Shin 2017 14 11.9 42 13 12.6 43 0.9% 1.00 [-4.21 , 6.21]
Murki 2018 5 4 133 5 3 139 33.3% 0.00 [-0.84 , 0.84]
Manley 2019 4.8 2.5 185 5.2 4 194 53.0% -0.40 [-1.07 , 0.27]
Total (95% CI) 854 887 100.0% -0.27 [-0.76 , 0.22]

(CPAP) for primary respiratory support in preterm infants, Outcome 16: Retinopathy of prematurity

Demirel 2019 2 53 1 54 8.5% 0.02 [-0.04 , 0.08]

Lavizzari 2016 1 158 0 158 25.1% 0.01 [-0.01 , 0.02]
Murki 2018 6 133 7 139 21.6% -0.01 [-0.06 , 0.05]
Roberts 2016 0 278 1 286 44.8% -0.00 [-0.01 , 0.01]
Total (95% CI) 622 637 100.0% 0.00 [-0.01 , 0.01]

Total events: 9 9
Informed decisions.
airway pressure (CPAP) for primary respiratory support in preterm infants, Outcome
17: Subgroup analysis – mechanical ventilation with or without surfactant permitted

1.17.1 Surfactant permitted

Lavizzari 2016 17 158 15 158 13.0% 1.13 [0.59 , 2.19]
Farhat 2018 15 54 14 53 12.3% 1.05 [0.56 , 1.96]
Murki 2018 8 133 11 139 9.4% 0.76 [0.32 , 1.83]
Armanian 2019 5 35 12 37 10.1% 0.44 [0.17 , 1.12]
Demirel 2019 5 53 7 54 6.0% 0.73 [0.25 , 2.15]
Subtotal (95% CI) 433 441 50.9% 0.86 [0.61 , 1.21]
Total events: 50 59
1.17.2 Surfactant not permitted

Yoder 2013 6 58 9 67 7.3% 0.77 [0.29 , 2.03]
Roberts 2016 43 278 35 286 30.0% 1.26 [0.84 , 1.91]
Manley 2019 17 185 14 194 11.9% 1.27 [0.65 , 2.51]
Subtotal (95% CI) 521 547 49.1% 1.19 [0.86 , 1.66]
Total events: 66 58
Total (95% CI) 954 988 100.0% 1.02 [0.81 , 1.30]

Heterogeneity: Chi² = 5.77, df = 7 (P = 0.57); I² = 0% 0.1 0.2 0.5 1 2 5 10
Informed decisions.
Analysis 1.18. Comparison 1: Nasal high flow (nHF) compared with continuous
positive airway pressure (CPAP) for primary respiratory support in preterm infants,
Outcome 18: Subgroup analysis – pneumothorax with or without surfactant permitted

1.18.1 Surfactant not permitted

Nair 2005 0 33 2 34 6.5% 0.21 [0.01 , 4.13]
Yoder 2013 0 58 3 67 8.6% 0.16 [0.01 , 3.12]
Roberts 2016 0 278 6 286 17.0% 0.08 [0.00 , 1.40]
Shin 2017 2 42 0 43 1.3% 5.12 [0.25 , 103.50]
Manley 2019 6 185 9 194 23.3% 0.70 [0.25 , 1.93]
Subtotal (95% CI) 596 624 56.7% 0.48 [0.23 , 1.00]
Total events: 8 20
1.18.2 Surfactant permitted

Lavizzari 2016 3 158 4 158 10.6% 0.75 [0.17 , 3.30]
Murki 2018 0 133 1 139 3.9% 0.35 [0.01 , 8.47]
Farhat 2018 7 54 5 53 13.4% 1.37 [0.47 , 4.06]
Demirel 2019 2 53 1 54 2.6% 2.04 [0.19 , 21.81]
Armanian 2019 2 35 5 37 12.9% 0.42 [0.09 , 2.04]
Subtotal (95% CI) 433 441 43.3% 0.89 [0.45 , 1.76]
Total events: 14 16
Total (95% CI) 1029 1065 100.0% 0.66 [0.40 , 1.08]

Total events: 22 36
Informed decisions.
airway pressure (CPAP) for primary respiratory support in preterm infants, Outcome 19:
Subgroup analysis – mechanical ventilation with or without second-line CPAP permitted

1.19.1 Rescue CPAP permitted

Roberts 2016 43 278 35 286 28.3% 1.26 [0.84 , 1.91]
Murki 2018 8 133 11 139 8.8% 0.76 [0.32 , 1.83]
Manley 2019 17 185 14 194 11.2% 1.27 [0.65 , 2.51]
Subtotal (95% CI) 596 619 48.3% 1.17 [0.85 , 1.63]
Total events: 68 60
1.19.2 Rescue CPAP not permitted

Yoder 2013 6 58 9 67 6.8% 0.77 [0.29 , 2.03]
Lavizzari 2016 17 158 15 158 12.3% 1.13 [0.59 , 2.19]
Farhat 2018 15 54 14 53 11.6% 1.05 [0.56 , 1.96]
Sharma 2019 6 50 7 50 5.7% 0.86 [0.31 , 2.37]
Demirel 2019 5 53 7 54 5.7% 0.73 [0.25 , 2.15]
Armanian 2019 5 35 12 37 9.6% 0.44 [0.17 , 1.12]
Subtotal (95% CI) 408 419 51.7% 0.86 [0.62 , 1.20]
Total events: 54 64
Total (95% CI) 1004 1038 100.0% 1.01 [0.80 , 1.28]

Comparison 2. Nasal high flow (nHF) compared with nasal intermittent positive pressure ventilation (NIPPV) for
primary respiratory support in preterm infants
pants
2.1 Death or bronchopul- 2 182 Risk Difference (M-H, Fixed, 95% -0.05 [-0.14, 0.04]
monary dysplasia CI)
2.1.1 < 28 weeks 1 3 Risk Difference (M-H, Fixed, 95% 0.50 [-0.32, 1.32]
CI)
2.1.2 28–32 weeks 1 28 Risk Difference (M-H, Fixed, 95% -0.02 [-0.22, 0.18]
CI)
2.1.3 ≥ 32 weeks 1 44 Risk Difference (M-H, Fixed, 95% 0.00 [-0.08, 0.08]
CI)
2.1.4 < 37 weeks (no subgroup 1 107 Risk Difference (M-H, Fixed, 95% -0.10 [-0.23, 0.04]
data available) CI)
Informed decisions.
pants
2.2 Death 3 254 Risk Difference (M-H, Fixed, 95% -0.02 [-0.10, 0.05]
CI)
2.2.1 < 28 weeks 1 3 Risk Difference (M-H, Fixed, 95% 0.00 [-0.73, 0.73]
CI)
2.2.2 28–32 weeks 1 28 Risk Difference (M-H, Fixed, 95% 0.00 [-0.13, 0.13]
CI)
2.2.3 ≥ 32 weeks 1 44 Risk Difference (M-H, Fixed, 95% 0.00 [-0.08, 0.08]
CI)
2.2.4 < 37 weeks (subgroup da- 2 179 Risk Difference (M-H, Fixed, 95% -0.03 [-0.13, 0.07]
ta not available) CI)
2.3 Bronchopulmonary dyspla- 3 271 Risk Ratio (M-H, Fixed, 95% CI) 1.19 [0.66, 2.12]
sia
2.3.1 < 28 weeks 1 3 Risk Ratio (M-H, Fixed, 95% CI) 1.50 [0.38, 6.00]
2.3.3 ≥ 32 weeks 1 0 Risk Ratio (M-H, Fixed, 95% CI) Not estimable
2.3.4 < 37 weeks (no subgroup 1 107 Risk Ratio (M-H, Fixed, 95% CI) 0.98 [0.26, 3.72]
data available)
2.4 Treatment failure within 72 4 343 Risk Ratio (M-H, Fixed, 95% CI) 1.27 [0.90, 1.79]
hours of trial entry
2.4.3 > 32 weeks 1 44 Risk Ratio (M-H, Fixed, 95% CI) 0.91 [0.33, 2.55]
data available)
2.5 Mechanical ventilation 4 343 Risk Ratio (M-H, Fixed, 95% CI) 0.91 [0.62, 1.33]
within 72 hours of trial entry
data available)
2.6 Mechanical ventilation at 2 183 Risk Ratio (M-H, Fixed, 95% CI) 0.81 [0.56, 1.17]
any time point after trial entry
2.7 Surfactant treatment 4 344 Risk Ratio (M-H, Fixed, 95% CI) 0.90 [0.71, 1.15]
Informed decisions.
pants
2.8 Duration of hospitalisation 1 76 Mean Difference (IV, Fixed, 95% 1.00 [-9.10, 11.10]
(days) CI)
2.9 Pneumothorax 4 344 Risk Ratio (M-H, Fixed, 95% CI) 0.78 [0.40, 1.53]
2.10 Nasal trauma 3 272 Risk Difference (M-H, Fixed, 95% -0.17 [-0.24, -0.10]
CI)
2.11 Nosocomial sepsis 2 183 Risk Ratio (M-H, Fixed, 95% CI) 0.69 [0.28, 1.74]
2.12 Gastrointestinal perfora- 2 165 Risk Ratio (M-H, Fixed, 95% CI) 1.88 [0.41, 8.65]
tion or severe necrotising en-
terocolitis
2.13 Time to full feeds (days) 1 76 Mean Difference (IV, Fixed, 95% 1.70 [-1.21, 4.61]
CI)
2.14 Duration of respiratory 0 Other data No numeric data

support (days)
2.15 Duration of supplemental 0 Other data No numeric data

oxygen (days)
Informed decisions.
Analysis 2.1. Comparison 2: Nasal high flow (nHF) compared with nasal intermittent positive pressure ventilation
(NIPPV) for primary respiratory support in preterm infants, Outcome 1: Death or bronchopulmonary dysplasia
nHF NIPPV Risk Difference Risk Difference

2.1.1 < 28 weeks

Kugelman 2015 1 1 1 2 1.5% 0.50 [-0.32 , 1.32]
Subtotal (95% CI) 1 2 1.5% 0.50 [-0.32 , 1.32]
Total events: 1 1
Heterogeneity: Not applicable
2.1.2 28–32 weeks

Kugelman 2015 1 16 1 12 15.2% -0.02 [-0.22 , 0.18]
Subtotal (95% CI) 16 12 15.2% -0.02 [-0.22 , 0.18]
Total events: 1 1
2.1.3 ≥ 32 weeks
Kugelman 2015 0 21 0 23 24.3% 0.00 [-0.08 , 0.08]
Subtotal (95% CI) 21 23 24.3% 0.00 [-0.08 , 0.08]
Total events: 0 0
2.1.4 < 37 weeks (no subgroup data available)

Farhat 2018 6 54 11 53 59.1% -0.10 [-0.23 , 0.04]
Subtotal (95% CI) 54 53 59.1% -0.10 [-0.23 , 0.04]
Total events: 6 11
Total (95% CI) 92 90 100.0% -0.05 [-0.14 , 0.04]

Total events: 8 13
Heterogeneity: Chi² = 3.71, df = 3 (P = 0.29); I² = 19% -2 -1 0 1 2
Test for overall effect: Z = 1.13 (P = 0.26) Favours nHF Favours NIPPV
Informed decisions.
Analysis 2.2. Comparison 2: Nasal high flow (nHF) compared with nasal intermittent positive
pressure ventilation (NIPPV) for primary respiratory support in preterm infants, Outcome 2: Death

2.2.1 < 28 weeks

Kugelman 2015 0 1 0 2 1.1% 0.00 [-0.73 , 0.73]
Subtotal (95% CI) 1 2 1.1% 0.00 [-0.73 , 0.73]
Total events: 0 0
2.2.2 28–32 weeks

Kugelman 2015 0 16 0 12 10.8% 0.00 [-0.13 , 0.13]
Subtotal (95% CI) 16 12 10.8% 0.00 [-0.13 , 0.13]
Total events: 0 0
2.2.3 ≥ 32 weeks
Kugelman 2015 0 21 0 23 17.4% 0.00 [-0.08 , 0.08]
Subtotal (95% CI) 21 23 17.4% 0.00 [-0.08 , 0.08]
Total events: 0 0

Farhat 2018 6 54 7 53 42.3% -0.02 [-0.14 , 0.10]
Armanian 2019 4 35 6 37 28.4% -0.05 [-0.21 , 0.11]
Subtotal (95% CI) 89 90 70.7% -0.03 [-0.13 , 0.07]
Total events: 10 13
Total (95% CI) 127 127 100.0% -0.02 [-0.10 , 0.05]

Total events: 10 13
Heterogeneity: Chi² = 0.49, df = 4 (P = 0.97); I² = 0% -1 -0.5 0 0.5 1
Informed decisions.
Analysis 2.3. Comparison 2: Nasal high flow (nHF) compared with nasal intermittent positive pressure
ventilation (NIPPV) for primary respiratory support in preterm infants, Outcome 3: Bronchopulmonary dysplasia
nHF NIPPV Risk Ratio Risk Ratio

2.3.1 < 28 weeks

Kugelman 2015 1 1 1 2 7.5% 1.50 [0.38 , 6.00]
Subtotal (95% CI) 1 2 7.5% 1.50 [0.38 , 6.00]
Total events: 1 1
2.3.2 28–32 weeks

Kugelman 2015 1 16 1 12 7.1% 0.75 [0.05 , 10.82]
Wang 2018 12 43 10 46 60.2% 1.28 [0.62 , 2.66]
Subtotal (95% CI) 59 58 67.4% 1.23 [0.61 , 2.48]
Total events: 13 11
2.3.3 ≥ 32 weeks
Kugelman 2015 0 21 0 23 Not estimable
Subtotal (95% CI) 0 0 Not estimable
Total events: 0 0
Test for overall effect: Not applicable

Farhat 2018 4 54 4 53 25.2% 0.98 [0.26 , 3.72]
Subtotal (95% CI) 54 53 25.2% 0.98 [0.26 , 3.72]
Total events: 4 4
Total (95% CI) 135 136 100.0% 1.19 [0.66 , 2.12]

Total events: 18 16
Informed decisions.
Analysis 2.4. Comparison 2: Nasal high flow (nHF) compared with nasal
intermittent positive pressure ventilation (NIPPV) for primary respiratory support
in preterm infants, Outcome 4: Treatment failure within 72 hours of trial entry

2.4.1 < 28 weeks

Kugelman 2015 1 1 2 2 5.0% 1.00 [0.39 , 2.58]
Subtotal (95% CI) 1 2 5.0% 1.00 [0.39 , 2.58]
Total events: 1 2
2.4.2 28–32 weeks

Kugelman 2015 6 16 5 12 14.2% 0.90 [0.36 , 2.26]
Wang 2018 4 43 4 46 9.6% 1.07 [0.29 , 4.01]
Subtotal (95% CI) 59 58 23.8% 0.97 [0.45 , 2.09]
Total events: 10 9
2.4.3 > 32 weeks

Kugelman 2015 5 21 6 23 14.2% 0.91 [0.33 , 2.55]
Subtotal (95% CI) 21 23 14.2% 0.91 [0.33 , 2.55]
Total events: 5 6

Farhat 2018 15 54 15 53 37.6% 0.98 [0.53 , 1.80]
Armanian 2019 19 35 8 37 19.3% 2.51 [1.27 , 4.98]
Subtotal (95% CI) 89 90 57.0% 1.50 [0.96 , 2.33]
Total events: 34 23
Total (95% CI) 170 173 100.0% 1.27 [0.90 , 1.79]

Total events: 50 40
Informed decisions.
Analysis 2.5. Comparison 2: Nasal high flow (nHF) compared with nasal intermittent
positive pressure ventilation (NIPPV) for primary respiratory support in preterm
infants, Outcome 5: Mechanical ventilation within 72 hours of trial entry

2.5.1 < 28 weeks

Kugelman 2015 1 1 2 2 5.0% 1.00 [0.39 , 2.58]
Subtotal (95% CI) 1 2 5.0% 1.00 [0.39 , 2.58]
Total events: 1 2
2.5.2 28–32 weeks

Kugelman 2015 6 16 5 12 14.2% 0.90 [0.36 , 2.26]
Wang 2018 4 43 4 46 9.6% 1.07 [0.29 , 4.01]
Subtotal (95% CI) 59 58 23.8% 0.97 [0.45 , 2.09]
Total events: 10 9
2.5.3 ≥ 32 weeks
Kugelman 2015 5 21 6 23 14.2% 0.91 [0.33 , 2.55]
Subtotal (95% CI) 21 23 14.2% 0.91 [0.33 , 2.55]
Total events: 5 6

Farhat 2018 15 54 15 53 37.6% 0.98 [0.53 , 1.80]
Armanian 2019 5 35 8 37 19.3% 0.66 [0.24 , 1.83]
Subtotal (95% CI) 89 90 57.0% 0.87 [0.52 , 1.47]
Total events: 20 23
Total (95% CI) 170 173 100.0% 0.91 [0.62 , 1.33]

Total events: 36 40
Informed decisions.
infants, Outcome 6: Mechanical ventilation at any time point after trial entry

Kugelman 2015 11 38 13 38 33.1% 0.85 [0.44 , 1.65]

Farhat 2018 21 54 26 53 66.9% 0.79 [0.51 , 1.22]
Total (95% CI) 92 91 100.0% 0.81 [0.56 , 1.17]

Total events: 32 39
ventilation (NIPPV) for primary respiratory support in preterm infants, Outcome 7: Surfactant treatment

Armanian 2019 22 35 25 37 34.5% 0.93 [0.66 , 1.31]

Farhat 2018 26 54 29 53 41.6% 0.88 [0.61 , 1.27]
Kugelman 2015 11 38 13 38 18.5% 0.85 [0.44 , 1.65]
Wang 2018 4 43 4 46 5.5% 1.07 [0.29 , 4.01]
Total (95% CI) 170 174 100.0% 0.90 [0.71 , 1.15]

Total events: 63 71
(NIPPV) for primary respiratory support in preterm infants, Outcome 8: Duration of hospitalisation (days)
nHF NIPPV Mean Difference Mean Difference

Kugelman 2015 39.2 22 38 38.2 22.9 38 100.0% 1.00 [-9.10 , 11.10]
Total (95% CI) 38 38 100.0% 1.00 [-9.10 , 11.10]

Test for subgroup differences: Not applicable Favours nHF Favours NIPPV
Informed decisions.
ventilation (NIPPV) for primary respiratory support in preterm infants, Outcome 9: Pneumothorax

Kugelman 2015 2 38 0 38 2.9% 5.00 [0.25 , 100.80]

Farhat 2018 7 54 9 53 52.4% 0.76 [0.31 , 1.90]
Wang 2018 2 43 4 46 22.3% 0.53 [0.10 , 2.77]
Armanian 2019 2 35 4 37 22.4% 0.53 [0.10 , 2.71]
Total (95% CI) 170 174 100.0% 0.78 [0.40 , 1.53]

Total events: 13 17
ventilation (NIPPV) for primary respiratory support in preterm infants, Outcome 10: Nasal trauma

Kugelman 2015 0 38 0 38 28.0% 0.00 [-0.05 , 0.05]

Farhat 2018 5 54 21 53 39.4% -0.30 [-0.46 , -0.15]
Wang 2018 1 43 8 46 32.7% -0.15 [-0.27 , -0.03]
Total (95% CI) 135 137 100.0% -0.17 [-0.24 , -0.10]

Total events: 6 29
Heterogeneity: Chi² = 46.96, df = 2 (P < 0.00001); I² = 96% -1 -0.5 0 0.5 1
Test for overall effect: Z = 4.54 (P < 0.00001) Favours nHF Favours NIPPV
ventilation (NIPPV) for primary respiratory support in preterm infants, Outcome 11: Nosocomial sepsis

Kugelman 2015 4 38 3 38 29.8% 1.33 [0.32 , 5.56]

Farhat 2018 3 54 7 53 70.2% 0.42 [0.11 , 1.54]
Total (95% CI) 92 91 100.0% 0.69 [0.28 , 1.74]

Total events: 7 10
Informed decisions.
infants, Outcome 12: Gastrointestinal perforation or severe necrotising enterocolitis

Kugelman 2015 2 38 0 38 20.6% 5.00 [0.25 , 100.80]

Wang 2018 2 43 2 46 79.4% 1.07 [0.16 , 7.26]
Total (95% CI) 81 84 100.0% 1.88 [0.41 , 8.65]

Total events: 4 2
ventilation (NIPPV) for primary respiratory support in preterm infants, Outcome 13: Time to full feeds (days)
nHF NIPPV Mean Difference Mean Difference

Kugelman 2015 13.5 5.5 38 11.8 7.3 38 100.0% 1.70 [-1.21 , 4.61]
Total (95% CI) 38 38 100.0% 1.70 [-1.21 , 4.61]

Test for subgroup differences: Not applicable Favours nHF Favours NIPPV
(NIPPV) for primary respiratory support in preterm infants, Outcome 14: Duration of respiratory support (days)
Duration of respiratory support (days)
Study Nasal HF – median (IQR) NIPPV – median (IQR)
Kugelman 2015 4 (1-15) 2 (0.3-6.5)
(NIPPV) for primary respiratory support in preterm infants, Outcome 15: Duration of supplemental oxygen (days)
Duration of supplemental oxygen (days)
Study Nasal HF – median (IQR) NIPPV – median (IQR)
Wang 2018 13.7 (4.9-29) 12.6 (5.4-25.8)
APPENDICES
Appendix 1. Search strategies 2022
MEDLINE strategy
Informed decisions.
(Continued)
Ovid MEDLINE(R) and Epub Ahead of Print, In-Process, In-Data-Review & Other Non-Indexed Citations, Daily and Versions <1946 to
March 11, 2022>
1 (high flow or high frequency or high gas flow or high gas flows).mp. (101096)
2 (nasal or binasal).mp. (143205)
3 exp Nasal Cavity/ (12366)
4 exp Nasal Mucosa/ (27389)
5 2 or 3 or 4 (150606)
6 (cannula* or prong*).mp. (52383)
7 exp Catheters/ or exp Cannula/ or exp Catheterization/ (223676)
8 6 or 7 (264567)
9 1 and 5 and 8 (2021)
10 (Optiflow or Vapotherm or (Fisher adj2 Paykel)).mp. (193)
11 (hfnc or hfnp or hhfnox or HHHFNC).mp. (937)
12 9 or 10 or 11 (2192)
13 exp infant, newborn/ (648472)
14 (newborn* or new born or new borns or newly born or baby* or babies or premature or prematurity or preterm or pre term or low
birth weight or low birthweight or VLBW or LBW or infant or infants or "infant s" or infant's or infantile or infancy or neonat*).ti,ab.
(912282)
15 13 or 14 (1203411)
16 randomized controlled trial.pt. (561036)
17 controlled clinical trial.pt. (94734)
18 randomized.ab. (553471)
19 placebo.ab. (226281)
20 drug therapy.fs. (2455314)
21 randomly.ab. (377656)
22 trial.ab. (590648)
23 groups.ab. (2321557)
24 or/16-23 (5285012)
25 exp animals/ not humans.sh. (4970671)
Informed decisions.
(Continued)
26 24 not 25 [RCT Filter] (4598867)
27 15 and 26 (206591)
28 12 and 27 (219)
CINAHL (Ebsco)
Search date: March 12, 2022
S1 ( (("high flow" OR "high frequency" OR "high gas flow" OR "high gas flows") 136
AND (nasal OR binasal) AND (cannula* OR prong*)) OR ((Optiflow OR
Vapotherm OR (Fisher AND Paykel))) OR (hfnc OR hfnp OR hhfnox OR HH-
HFNC)) ) AND ( (infant or infants or infantís or infantile or infancy or newborn*
or "new born" or "new borns" or "newly born" or neonat* or baby* or babies
or premature or prematures or prematurity or preterm or preterms or "pre
term" or premies or "low birth weight" or "low birthweight" or VLBW or LBW)
AND (randomized controlled trial OR controlled clinical trial OR randomized
OR randomised OR placebo OR clinical trials as topic OR randomly OR trial OR
PT clinical trial) )
Cochrane CENTRAL via CRS

Search date: 12 March 2022
Cochrane CENTRAL via CRS
12-Mar-22
1 high flow or high frequency or high gas flow or high gas flows AND CEN- 8584
TRAL:TARGET
2 nasal or binasal AND CENTRAL:TARGET 21415
3 MESH DESCRIPTOR Nasal Cavity EXPLODE ALL AND CENTRAL:TARGET 428
4 MESH DESCRIPTOR Nasal Mucosa EXPLODE ALL AND CENTRAL:TARGET 1003
5 #2 OR #3 OR #4 21455
6 cannula* or prong* AND CENTRAL:TARGET 6609
7 MESH DESCRIPTOR Catheters EXPLODE ALL AND CENTRAL:TARGET 1983
8 MESH DESCRIPTOR Cannula EXPLODE ALL AND CENTRAL:TARGET 164
9 MESH DESCRIPTOR Catheterization EXPLODE ALL AND CENTRAL:TARGET 9846
10 #6 OR #7 OR #8 OR #9 16564
Informed decisions.
(Continued)
11 #5 AND #10 AND #1 1265
12 (Optiflow or Vapotherm or (Fisher ADJ2 Paykel)) AND CENTRAL:TARGET 300
13 hfnc or hfnp or hhfnox or HHHFNC AND CENTRAL:TARGET 666
14 #11 OR #12 OR #13 1502
15 MESH DESCRIPTOR Infant, Newborn EXPLODE ALL AND CENTRAL:TARGET 17489
16 infant or infants or infant's or "infant s" or infantile or infancy or newborn* or 96314

"new born" or "new borns" or "newly born" or neonat* or baby* or babies or
premature or prematures or prematurity or preterm or preterms or "pre term"
or premies or "low birth weight" or "low birthweight" or VLBW or LBW or ELBW
or NICU AND CENTRAL:TARGET
17 #15 OR #16 96314
18 #14 AND #17 446
Appendix 2. Risk of bias tool

We used the Cochrane RoB 1 tool (Higgins 2011).
Sequence generation (checking for possible selection bias). Was the allocation sequence adequately generated?
For each included study, we categorised the method used to generate the allocation sequence as:
• low risk (any truly random process, e.g. random number table; computer random number generator);
• high risk (any non-random process, e.g. odd or even date of birth; hospital or clinic record number); or
• unclear risk.
Allocation concealment (checking for possible selection bias). Was allocation adequately concealed?
For each included study, we categorised the method used to conceal the allocation sequence as:
• low risk (e.g. telephone or central randomisation; consecutively numbered sealed opaque envelopes);
• high risk (open random allocation; unsealed or non-opaque envelopes, alternation; date of birth); or
• unclear risk.
Blinding of participants and personnel (checking for possible performance bias). Was knowledge of the allocated intervention
adequately prevented during the study?
For each included study, we categorised the methods used to blind study participants and personnel from knowledge of which intervention
a participant received. Blinding was assessed separately for different outcomes or class of outcomes. We categorised the methods as:
• low risk, high risk or unclear risk for participants; and

• low risk, high risk or unclear risk for personnel.
Blinding of outcome assessment (checking for possible detection bias). Was knowledge of the allocated intervention adequately
prevented at the time of outcome assessment?
For each included study, we categorised the methods used to blind outcome assessment. Blinding was assessed separately for different
outcomes or class of outcomes. We categorised the methods as:
• low risk for outcome assessors;

• high risk for outcome assessors; or
• unclear risk for outcome assessors.
Informed decisions.
Incomplete outcome data (checking for possible attrition bias through withdrawals, dropouts, protocol deviations). Were
incomplete outcome data adequately addressed?
For each included study and for each outcome, we described the completeness of data including attrition and exclusions from the analysis.
We noted whether attrition and exclusions were reported, the numbers included in the analysis at each stage (compared with the total
randomised participants), reasons for attrition or exclusion where reported, and whether missing data were balanced across groups or
were related to outcomes. Where sufficient information was reported or supplied by the trial authors, we re-included missing data in the
analyses. We categorised the methods as:
• low risk (less than 20% missing data);

• high risk (20% or greater missing data); or
• unclear risk.
Selective reporting bias. Are reports of the study free of suggestion of selective outcome reporting?
For each included study, we described how we investigated the possibility of selective outcome reporting bias and what we found. For
studies in which study protocols were published in advance, we compared prespecified outcomes versus outcomes eventually reported in
the published results. If the study protocol was not published in advance, we contacted study authors to gain access to the study protocol.
We assessed the methods as:
• low risk (where it is clear that all of the study's prespecified outcomes and all expected outcomes of interest to the review have been
reported);
• high risk (where not all the study's prespecified outcomes have been reported; one or more reported primary outcomes were not
prespecified outcomes of interest and are reported incompletely and so cannot be used; study fails to include results of a key outcome
that would have been expected to have been reported); or
• unclear risk.
Other sources of bias. Was the study apparently free of other problems that could put it at a high risk of bias?
For each included study, we described any important concerns we had about other possible sources of bias (for example, whether there
was a potential source of bias related to the specific study design or whether the trial was stopped early due to some data-dependent
process). We assessed whether each study was free of other problems that could put it at risk of bias as:
• low risk;
• high risk; or
• unclear risk.
If needed, we explored the impact of the level of bias through undertaking sensitivity analyses.
WHAT'S NEW
Date Event Description
5 May 2023 New citation required and conclusions Nasal HF is associated with a higher rate of treatment failure, but
have changed not mechanical ventilation, compared with CPAP. There is little
evidence for the use of nHF as primary respiratory support in ex-
tremely preterm infants.
5 May 2023 New search has been performed We updated the search in March 2022, and identified the 13 stud-
ies (total of 2540 preterm infants) included in this review. Meth-
ods altered to include only studies of nasal high flow for primary
respiratory support (not postextubation or postsurfactant sup-
port).
HISTORY
Protocol first published: Issue 1, 2007
Review first published: Issue 5, 2011
Informed decisions.
Date Event Description
1 March 2016 New search has been performed This updates the review "High flow nasal cannula for respiratory
support in preterm infants". (Wilkinson 2011).
1 March 2016 New citation required and conclusions Updated search January 2016.
have changed
14 February 2012 Amended Correction to denominator in Comparison 2.

Figures reordered.
CONTRIBUTIONS OF AUTHORS
The protocol was developed by Wilkinson, Andersen and O'Donnell (Wilkinson 2007).
Kate Hodgson and Brett Manley conducted screening for the 2022 update, and performed the GRADE assessment, with any uncertainty
resolved by Dominic Wilkinson.
For the articles in which BJM had a conflict of interest due to authorship, KH and DW performed the GRADE assessment.
All authors (KH, BJM, AGDP, DW) provided data analysis and collaborated in the writing of the review.
For the articles in which BJM had a conflict of interest due to authorship, the other authors (KH, AGDP, DW) performed the data analysis.
DECLARATIONS OF INTEREST
KH works as a Neonatologist, Royal Women's Hospital, Royal Children's Hospital (PIPER retrieval). She is PhD candidate, currently
undertaking a PhD in neonatal high flow. Her PhD main area of study is an RCT of high flow during neonatal endotracheal intubation;
equipment for this is supplied by Vapotherm. Vapotherm had no input into the trial design, nor access to trial data or the manuscript prior
to publication. This trial is not eligible for inclusion in this review. KH has been a co-author on review articles and book chapters which
include descriptions of nasal high flow.
BJM has published several original research articles, review articles and editorials on the topic of nasal high flow in peer-reviewed journals.
He works as a Consultant Neonatologist at the Royal Women's Hospital, Parkville, Victoria, Australia. BJM is one of KH's PhD supervisors,
and is a co-investigator on the RCT of high flow during neonatal endotracheal intubation. This trial is not eligible for inclusion in this review.
BM was an author of two of the trials included in this review (Manley 2019; Roberts 2016). These studies were funded by NHMRC (Australia).
Analysis of those papers was performed by other review authors (DW, AGDP and KH).
AGDP works as a Consultant Neonatologist, Royal Hobart Hospital, Tasmania, Australia.
DW works as a Consultant Neonatologist, John Radcliffe Hospital, Oxford, UK.
SOURCES OF SUPPORT
Internal sources
• University of Oxford, UK
DW has University of Oxford affiliation.

• Royal Women's Hospital, Australia
KH and BM are employed by the Royal Women's Hospital, Melbourne.

• University of Melbourne, Australia
BM is an Associate Professor at the University of Melbourne. KH is undertaking a PhD through the University of Melbourne.
• NHMRC, Australia
KH has received salary support via a National Health and Medical Research Council (NHMRC) Australia grant. Her salary support includes
funding for A/Prof Brett Manley (supervisor) via NHMRC.
• University of Melbourne, Australia
Informed decisions.
KH received support from the University of Melbourne Henry and Rachel Ackman Travel Scholarship for attendance at the jENS Congress
2019.
BJM received a Government career development grant fellowship from the Medical Research Future Fund (Australia), and a project
grant from NHMRC (Australia).
External sources
Fellowship - DW, BM
• Vermont Oxford Network, USA
Cochrane Neonatal Reviews are produced with support from Vermont Oxford Network, a worldwide collaboration of health
professionals dedicated to providing evidence-based care of the highest quality for newborn infants and their families.
DIFFERENCES BETWEEN PROTOCOL AND REVIEW

• For the 2022 review update, we added the methodology and plan for summary of findings tables and GRADE recommendations, which
were not included in the previous versions of the review. These changes were to comply with the latest Cochrane standards.
• For the 2022 review update, we developed a new search strategy, which we ran without date limits (Appendix 1).
• The protocol and earlier versions of this review included Embase as a search source. This update omitted Embase based on the rationale
that CENTRAL now includes records from Embase. This rationale has, subsequently, been flagged as a method which may reduce
sensitivity of the search. Subsequent updates will include Embase as a source.
• The previous versions of this review included the use of nHF for other indications in preterm infants (Wilkinson 2011; Wilkinson 2016).
Due to the increase in number of studies of nHF in preterm infants, this review is limited to studies of nHF as primary respiratory support.
The title has been updated to reflect this (previous title was 'High flow nasal cannula for respiratory support in preterm infants'). A
second review (yet to be completed) will examine nHF for postextubation or postsurfactant respiratory support.
• We updated the Criteria for considering studies for this review section to clarify that studies with a superiority, non-inferiority or
equivalence hypothesis could be included.
• The term 'chronic lung disease' has been changed to 'bronchopulmonary dysplasia'.
• The previous versions of this review also compared nHF with high flow delivered with alternative devices; this has been removed from
the current version of the review.
• Some changes have been made to the outcome measures from Wilkinson 2016 to this update:
◦ treatment failure and mechanical ventilation have been made primary outcomes (were secondary outcomes in the previous review);
◦ treatment failure and mechanical ventilation have been defined as occurring within 72 hours of trial entry (seven days in previous
review);
◦ surfactant administration (via any method) was added as a secondary outcome.
• The following headings or text were added or updated:
◦ unit of analysis;
◦ dealing with missing data;
◦ assessment of heterogeneity;
◦ assessment of reporting biases;
◦ data synthesis;
◦ potential biases in the review process;
◦ agreements and disagreements with other studies or reviews;
◦ summary of findings and assessment of certainty of the evidence.
• The summary of findings tables were added.
• Subgroups analyses were not present in the protocol, but were added to Wilkinson 2011 and modified in Wilkinson 2016.
• The subgroup analyses (for the primary outcomes) added with this update were:
◦ surfactant administration permitted during the intervention period (without this being deemed treatment failure) versus not
permitted;
◦ second-line CPAP permitted in the nHF arm prior to mechanical ventilation versus not permitted.
Informed decisions.
INDEX TERMS
Medical Subject Headings (MeSH)

*Bronchopulmonary Dysplasia [prevention & control]; Infant, Extremely Premature; Oxygen; *Pneumothorax [etiology]; Respiration,
Artificial [adverse effects]; Surface-Active Agents
MeSH check words

Humans; Infant, Newborn

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Nasal high flow therapy for primary respiratory support in preterm

Hodgson KA, Wilkinson D, De Paoli AG, Manley BJ

Hodgson KA, Wilkinson D, De Paoli AG, Manley BJ.

Nasal high flow therapy for primary respiratory support in preterm

Kate A Hodgson1,2, Dominic Wilkinson3,4, Antonio G De Paoli5, Brett J Manley1,2

Contact: Kate A Hodgson, kate.hodgson@thewomens.org.au.

Editorial group: Cochrane Neonatal Group.

Data collection and analysis

Nasal high flow compared with ambient oxygen

We found no studies examining this comparison.

Nasal high flow compared with low flow nasal cannulae

We found no studies examining this comparison.

PLAIN LANGUAGE SUMMARY

Nasal high flow therapy for breathing support in preterm babies

What is respiratory support and how is it treated?

What did we do?

What did we find?

What did we find?

What are the limitations of the evidence?

How up to date is this evidence?

The search is up to date as of 12 March 2022.

Patient or population: preterm infants requiring primary respiratory support

Outcomes Anticipated absolute effects* Relative effect № of partici- Certainty of Comments

Cochrane Database of Systematic Reviews

GRADE Working Group grades of evidence

Patient or population: preterm infants requiring primary respiratory support

Cochrane Database of Systematic Reviews

Outcomes Anticipated absolute effects* Relative effect № of partici- Certainty of Comments

GRADE Working Group grades of evidence

Cochrane Database of Systematic Reviews

BACKGROUND overdistension and pneumothorax from unmeasured positive end

OBJECTIVES disease' or 'CLD' without a clear accompanying definition were

Types of studies Secondary outcomes

Electronic searches The Cochrane Neonatal Group acknowledges that Embase is a

Figure 1. Study flow diagram.

801 records 17 records

598 references; 17 543 references; 4

Sensitivity analysis Results of the search

• death or BPD; See Figure 1 for details of study selection process.

Incomplete outcome data (attrition bias): All outcomes

Selective reporting (reporting bias)

Random sequence generation (selection bias)

0% 25% 50% 75% 100%

Low risk of bias Unclear risk of bias High risk of bias

Meta-analysis of data from two studies (total 182 infants) suggests

Sensitivity analyses Subgroup analyses for heterogeneity

Certainty of evidence (GRADE) Sensitivity analyses

Certainty of evidence (GRADE) Subgroup analyses for heterogeneity

Manley 2019 {published and unpublished data}

Pyon 2008 {published data only} References to studies awaiting assessment

NCT01270581 {unpublished data only} Ciuffini 2014

NCT02499744 {published data only} Conte 2018

GRADEpro GDT [Computer program] Jasin 2008

Roberts 2014 positive airway pressure in infants. Journal of Perinatology

* Indicates the major publication for the study

Characteristics of included studies [ordered by study ID]

Methods Randomised controlled trial

Participants 109 preterm neonates with BW < 1500 g; mean 30 weeks' GA

Nasal CPAP (37 infants): pressure 5–6 cmH2O

Armanian 2019 (Continued)

Notes Recruitment from February 2015 to March 2016 at 2 centres in Iran.

No funding stated, no conflicts of interest declared.