ADC-FNN Online First, published on December 23, 2016 as 10.
1136/archdischild-2016-311388
1
Department of Neonatology,
Coombe Women and Infants
University Hospital, Dublin,
Ireland
2
UCD School of Medicine,
University College Dublin,
Dublin, Ireland
3
Institute for the Care of
Mother and Child, Prague,
Czech Republic
4
3rd Faculty of Medicine,
Charles University, Prague,
Czech Republic
Correspondence to
Associate Clinical Professor
Jan Miletin, Department of
Neonatology, Coombe Women
and Infants University Hospital,
Cork Street, Dublin 8, Ireland;
miletinj@yahoo.com
Received 7 June 2016
Revised 24 September 2016
Accepted 29 November 2016
To cite: Glackin SJ,
O’Sullivan A, George S,
et al. Arch Dis Child Fetal
Neonatal Ed Published
Online First: [ please include
Day Month Year]
doi:10.1136/archdischild-
2016-311388
Glackin SJ, et al. Arch Dis Child Fetal Neonatal Ed 2016;0:F1–F4. doi:10.1136/archdischild-2016-311388
Copyright Article author (or their employer) 2016. Produced by BMJ Publishing Group Ltd (& RCPCH) under licence.
Original article
High flow nasal cannula versus NCPAP, duration
to full oral feeds in preterm infants: a randomised
controlled trial
Sinead J Glackin,1 Anne O’Sullivan,1 Sherly George,1,2 Jana Semberova,1,3
Jan Miletin1,2,3,4
ABSTRACT
Objective To compare the time taken by preterm
infants with evolving chronic lung disease to achieve full
oral feeding when supported with humidified high flow
nasal cannula (HFNC) or nasal continuous positive
airway pressure (NCPAP).
Design Single centre randomised controlled trial.
Setting Level III neonatal intensive care unit at the
Coombe Women and Infants University Hospital, Dublin,
Ireland.
Patients Very low birthweight (birth weight <1500 g)
infants born before 30 weeks’ gestation who were
NCPAP-dependent at 32 weeks corrected gestational age
were eligible to participate.
Interventions Enrolled infants were randomised in a
1:1 ratio to receive HFNC or NCPAP. Participants were
monitored daily until full oral feeding was established
and the baby was off respiratory support.
Main outcome measures Our primary outcome was
the number of days taken to establish full oral feeds
(defined as oral intake ≥120 mL/kg/day) from the time
of randomisation. We estimated that enrolling 44
subjects (22 in each group) would allow us demonstrate
a 7-day difference in our primary outcome with 80%
power and α of 5%.
Results Forty-four infants were randomised (22 to
HFNC vs 22 to NCPAP). The mean time to achieve full
oral feeding was not different between the groups
(HFNC 36.5 (±18.2) days vs NCPAP 34.1 (±11.2) days,
p=0.61).
Conclusions Preterm infants treated with HFNC did
not achieve full oral feeding more quickly than infants
treated with NCPAP.
Trial registration number ISRCTN66716753.
INTRODUCTION
Heated humidified high flow nasal cannula
(HFNC) is a widely used form of respiratory
support in preterm infants with respiratory distress
syndrome (RDS) as an alternative to other forms of
non-invasive ventilation (NIV). In a recently pub-
lished meta-analysis that included eight randomised
controlled trials (RCTs) and 1112 preterm infants,
HFNC was found to be as well tolerated as nasal
continuous positive airway pressure (NCPAP), the
most frequently used form of NIV in preterm
infants.1 No significant differences between HFNC
and NCPAP were found in terms of efficacy as
primary respiratory or postextubation support for
preterm infants with RDS. However, one of the
studies included in the meta-analysis showed that
What is already known on this topic?
▸ High flow nasal cannula therapy and nasal
continuous positive airway pressure (NCPAP)
are safe and effective respiratory support
options for preterm infants with respiratory
distress syndrome.
▸ High flow nasal cannula is less bulky than
NCPAP.
▸ Oral feeding is difficult for preterm infants on
respiratory support.
What this study adds?
▸ There is no advantage of high flow nasal
cannula therapy compared with NCPAP in
establishing oral feeds in preterm infants.
▸ It seems safe to feed orally stable preterm
infants on NCPAP.
while there was no difference in the failure rates of
HFNC and NCPAP, nearly half of those who failed
HFNC were successfully managed on NCPAP
without the need for subsequent reintubation.2
Although concerns have previously been
expressed about the safety of HFNC due to the dif-
ficulty in accurately measuring and controlling the
pressure generated, no differences in the rates of
pulmonary air leaks or death in preterm infants
were found.3 In the meta-analysis of five studies
involving 857 infants, HFNC was associated with a
significantly reduced risk of nasal trauma over
NCPAP.1
Several RCTs comparing HFNC and NCPAP
included time to attain full enteral feeding within
the secondary outcomes and did not find any sig-
nificant differences between the groups.4–6 Yoon
et al7 reported in their retrospective study
decreased time to reach full enteral feeds and
regain birth weight in the HFNC group. A poten-
tial advantage of HFNC over NCPAP is that it may
facilitate oral feeding and kangaroo care. Oral
feeding is usually trialled in infants older than
32 weeks corrected gestational age (CGA), when
they have developed the coordination for sucking,
swallowing and breathing. Many clinicians wait
until after infants are off NCPAP support before
F1
 Original article
offering oral feeds.8 9 Time to achieve full oral feeds was
reported as a secondary outcome in the RCT by Yoder et al.10
They did not find any significant differences between HFNC
and NCPAP in infants born between 28 and 42 weeks of gesta-
tion. Recently, Shetty et al8 reported quicker attainment of full
oral feeds using HFNC in preterm infants requiring non-
invasive respiratory support at 34 weeks of gestation in their
case series. However, this clinical question has not been tested
in an RCT to date. We hypothesised that preterm infants with
evolving chronic lung disease (CLD) treated with HFNC would
achieve full oral feeding earlier than preterm infants treated
with NCPAP.
PATIENTS AND METHODS
We conducted an RCT at the Coombe Women and Infants
University Hospital, Dublin, Ireland. The study was approved by
the hospital research ethics committee (reference number 18-2012)
and registered with the International Standard Randomized
Controlled Trial Number register (ISRCTN66716753) before the
first patient was enrolled.
Very low birthweight (VLBW) infants born before 30 weeks’
gestation who still received NCPAP respiratory support with
<30% oxygen at 32 weeks CGA and who were on full enteral
(≥120 mL/kg/day without supplemental intravenous nutrition),
orogastric tube feeding were eligible for enrolment. Infants who
were supported with a pressure <5 cm H2O with no supple-
mental oxygen requirement (FiO2=0.21) were trialled off
NCPAP. If these infants were restarted on NCPAP within
24 hours, they were eligible for randomisation. Infants with sig-
nificant congenital, respiratory, cardiac or airway abnormalities
or infants who were still on patient-assist NCPAP (added pres-
sure support breaths) were not eligible for enrolment.
Investigators, clinicians and caregivers were not masked to the
infant group assignment.
Written informed consent was obtained from the infant’s
parent or guardian prior to enrolment. Infants were randomised
at 32 weeks CGA, to continue on NCPAP at their current set-
tings (control group) or to HFNC commencing at 7 L/min with
oxygen as required to keep their oxygen saturation (SpO2)
between 88% and 95% (intervention group). HFNC was admi-
nistered using the Fabian Therapy Evolution (Acutronic Medical
Systems AG, Switzerland). Prongs were selected so as to sit
inside and occlude less than one-third of the nostrils as per the
manufacturer’s recommendations. NCPAP was administered
using the Fabian Therapy Evolution or the Infant Flow SiPAP
system (CareFusion, USA). NCPAP was given using nasal prongs
and/or masks of an appropriate size as per the manufacturer’s
recommendations. The treatment allocation schedule was gener-
ated using a statistical software package (StatsDirect V.2.6.1,
StatsDirect, UK) and was concealed from the treating clinicians.
Group assignment was written on cards and placed in sequen-
tially numbered, sealed opaque envelopes by an independent
administrative assistant. Immediately following enrolment, the
study investigator opened the next envelope in the sequence in
the presence of an attending physician and revealed the group
assignment. Enrolled infants were monitored until full oral
feeding was established. The monitoring included four hourly
observations of heart rate, respiratory rate, work of breathing,
oxygen requirement, frequency and duration of apnoeic epi-
sodes defined as breath holding for >20 s and daily physical
examinations. If any infant on HFNC deteriorated clinically, the
clinician on call was to assess the infant and determine whether
the infant was stable on HFNC, or if they needed to be
switched back to NCPAP along with any other required clinical
F2 Glackin SJ, et al. Arch Dis Child Fetal Neonatal Ed 2016;0:F1–F4. doi:10.1136/archdischild-2016-311388
investigations and management. If they were switched back to
NCPAP, they would remain on it for 48 hours before being
changed back to HFNC. If this occurred on more than two
occasions, these infants would remain on NCPAP until the end
of the trial. Infants were weaned off respiratory support at the
discretion of the attending clinicians and there were no specific
criteria mandated in the trial. Respiratory support was reinstated
if required, using these criteria: (a) more than one self-correcting
apnoeic episode per hour (defined as a bradycardia <100/min
with oxygen saturations (SpO2) <88% lasting >20 s); (b) one
apnoeic episode requiring either moderate stimulation or bag
and mask ventilation; (c) need for oxygen to maintain SpO2
>88%; (d) a score of 6–10 on the Silverman-Anderson
Respiratory Scale, indicating moderate-to-severe respiratory
distress.11
Oral feeds were offered in both groups at least once every
72 hours and additional feeds were offered when infants
demonstrated feeding cues (eg, sucking efficiently on a soother,
waking at feeding times and settling post feeds). Information on
every feed offered, including the type and adverse events (eg,
desaturation events—falls in oxygen saturation >10% from
baseline for >10 s; bradycardia—HR <100 bpm for >10 s),
were recorded on proforma data sheets.
Our primary aim was to establish if there was a difference
between infants on HFNC and infants on NCPAP in the dur-
ation it would take them to become fully established on full oral
feeds, either breast or bottle. Infants were determined to be
fully established on oral feeds when they had taken ≥120 mL/
kg/day by mouth for 24 hours. Our secondary objectives were:
the duration to the first attempted oral feed, the duration of
respiratory support, CLD defined as respiratory support at
36 weeks of gestational age, duration of hospital stay, episodes
of apnoea. We recorded basic demographic data (including ges-
tational age at birth, birth weight, Apgar scores, antenatal ster-
oids, mode of delivery). We have also recorded incidence of
RDS, need for endotracheal ventilation, incidence of patent
ductus arteriosus (defined as presence of patent ductus arterio-
sus beyond the first 72 hours of life), incidence of necrotising
enterocolitis (≥IIA according to modified Bell’s criteria)12 and
incidence of early onset sepsis (using definitions published in
the National Institute for Health and Care Excellence
guidelines).13
Our sample size was based on our primary outcome and our
end point was the number of days taken to establish full oral
feeds from the time of randomisation (32 weeks CGA). From a
retrospective chart review on our institution, we estimated that
it would take infants on NCPAP at 32 weeks CGA 35 days
(±8 days) to achieve full oral feeding (infants in this retrospect-
ive review were managed solely on NCPAP). We calculated that
in order to demonstrate a reduction of 7 days in our primary
outcome in infants receiving HFNC with 80% power and α
5%, we needed to enrol 44 subjects (22 in each group). We ana-
lysed outcome data using the ‘intention-to-treat’ principle with
StatsDirect, V.2.6.1 (StatsDirect) using Student’s t-test, Fisher’s
exact test and Mann-Whitney U test as appropriate.
RESULTS
There were 149 VLBW infants born at <30 weeks of gestation,
who had survived to 32 weeks of gestation during the recruit-
ment period ( January 2013 to December 2014). Of those, 59
infants were eligible for randomisation and 44 infants were ran-
domised to the trial (figure 1). There were no statistical differ-
ences between the NCPAP group and HFNC group in relation
to the patient characteristics at enrolment (table 1).
 Original article

The number of days taken to achieve full oral feeding was not
different between the groups (HFNC group 36.5 days±18.2 vs
NCPAP group 34.1 days±11.2, p=0.61).
There were no statistically significant differences between the
groups in terms of our predefined secondary outcomes (table 2).
Six infants (27%) in the NCPAP group were off respiratory
support when offered first oral feeds compared with one infant
(4.5%) in the HFNC group ( p=0.09). There were no other
adverse outcomes or events in any of the infants in either group
(including nasal trauma) in this study and no infants required to
be changed from HFNC to NCPAP due to clinical
deterioration.

DISCUSSION
Our hypothesis that there would be a difference of 7 days to
reach full oral feeds between the group randomised to NCPAP
and the group randomised to HFNC was rejected. While the
difference of 7 days may have seemed excessive, we were
looking for a clinically relevant result. A recent case series
looked at the establishment of full oral feeds as their primary
outcome in two groups of preterm infants with bronchopul-
monary dysplasia (defined as oxygen dependency beyond
28 days), managed either with NCPAP alone or with NCPAP for
2 weeks postextubation followed by HFNC.8 In their initial ana-
lysis, they found no difference between the two groups in the
duration to reach full oral feeds ( p>0.5). However, when they
compared infants still on respiratory support at 34 weeks, they
found that those on HFNC reached full oral feeds significantly
earlier than those on NCPAP (39.4 vs 41 weeks CGA;
p=0.002). However, this subgroup analysis result was likely
confounded by the fact that they waited to feed the NCPAP
infants until they were off respiratory support due to concern
Figure 1 Consort flow diagram of study enrolment. HFNC, high flow about aspiration, which may have led to some infants missing
nasal cannula; NCPAP, nasal continuous positive airway pressure. their opportunity to learn how to feed and developing oral aver-
sion. Their NCPAP group were also of earlier gestation and
lower birth weight, and therefore represented a different popu-
lation to the HFNC group.
Our results are supported by an RCT which included duration
Table 1 Patient characteristics at enrolment to reach full oral feeds in their secondary outcomes and found
HFNC NCPAP no difference in these results between the HFNC group and the
(n=22) (n=22) p Value

Gestational age at birth (weeks)* 26.9±1.5 27.3±1.5 0.41

Birth weight (g)* 868±160 891±202 0.68
Table 2 Primary and secondary outcomes
Apgar score 1st minute† 6 (5–7) 5 (4–6) 0.35 HFNC NCPAP
Apgar score 5th minute† 8 (7–8) 8 (6–8) 0.41 (n=22) (n=22) p Value
Complete course antenatal steroids‡ 77 86 0.7
Days to full oral feeds from enrolment 36.5±18.2 34.1±11.2 0.61
Caesarean delivery‡ 77 82 >0.99 (days)*
Respiratory distress syndrome‡ 100 100 NS First oral feed (days from enrolment)* 9.3±6.5 10.9±4.8 0.37
Endotracheal ventilation‡ 68 77 0.74 Days of respiratory support from 21.9±12.7 18.8±9.4 0.4
Patent ductus arteriosus‡ 91 67 0.07 enrolment (days)*
Necrotising enterocolitis (≥IIA)‡ 10 5 >0.99 Length of hospital stay from enrolment 80.4±17.3 78.2±14.1 0.68
Early onset sepsis‡ 9.5 5 >0.99 (days)*
Day of life at enrolment* 36±10 33±10 0.44 Chronic lung disease (at 36/40)† 64 68 >0.99
Weight at enrolment (g)* 1327±253 1272±181 0.42 Episodes of apnoea (episodes/day on 0 (0–0.036) 0.014 (0–0.151) 0.21
respiratory support)‡
*Mean±SD compared with t-test.
†Median (IQR) compared with Mann-Whitney U test. *Mean±SD compared with t-test.
‡n (%) compared with Fisher’s exact test. †n (%) compared with Fisher’s exact test.
HFNC, high flow nasal cannula; NCPAP, nasal continuous positive airway pressure; ‡Median (IQR) compared with Mann-Whitney U test.
NS, not significant. HFNC, high flow nasal cannula; NCPAP, nasal continuous positive airway pressure.

Glackin SJ, et al. Arch Dis Child Fetal Neonatal Ed 2016;0:F1–F4. doi:10.1136/archdischild-2016-311388 F3
 Original article
NCPAP group.10 In a retrospective study, Yoon et al7 found a
reduction in the duration to reach full enteral feeds in their
HFNC group. However, a major limitation of their study was
that there were only 55% of infants in the HFNC group actually
on HFNC.
One of the benefits of HFNC is the lack of nasal trauma to
infant’s friable mucosa. There were no episodes of nasal trauma
in either group in our study. This was likely due to the popula-
tion studied who were >32 weeks CGA and whose skin was less
friable and therefore at less risk of nasal trauma than younger
infants.
The results of our secondary outcomes are consistent with
other published studies, which have shown no difference in the
safety or efficacy of HFNC over NCPAP in stable preterm
infants. We also showed that there is no difference between the
groups in the duration of respiratory support requirement. In
some previous studies, infants on NCPAP were not offered oral
feeds due to concern about aspiration. We did not have any
cases of aspiration or acute respiratory deterioration following
oral feeds in either group. This is likely because of the stable
population of infants studied.
We did not get formal feedback from parents or nursing staff
in this study. Anecdotally, the nursing staff found it easier to
manage infants on HFNC in comparison to those on NCPAP
and the parents preferred HFNC as they had a clearer view of
their infant’s face, which facilitated bonding and kangaroo care.
In our neonatal unit, prior to the commencement of the RCT,
occasionally infants on NCPAP were cautiously commenced on
oral feeds if they were displaying feeding cues. Being part of the
RCT made the nursing staff more confident than they had been
prior to the trial to orally feed infants on NCPAP.
While we planned to include infants who were both bottle
and breast fed, we had disappointingly few infants who were
trialled on breast feeding and no infants who breast fed success-
fully. It is possible that if more infants were breast fed, it may
have influenced the results in favour of the HFNC group. The
low numbers of breast-fed infants likely reflects our general
population rather than either respiratory support mechanism.
The strengths of our study include the fact that it was an
RCT and it was safely conducted in an appropriate population
with proper observations and no infants were lost to follow-up.
Our selected population were a group of stable preterm infants
who were still NCPAP-dependent at 32 weeks CGA, as the
primary aim of the study was to determine the feeding outcome
of these infants.
The principal limitation of our study is that caregivers and
outcome assessors were not masked to the infants’ group assign-
ment. This introduced the potential for bias in that nursing staff
could offer extra feeds to infants who they felt were showing
feeding cues according to their preferred intervention. Most
nursing staff preferred handling the infants on HFNC, so they
could influence the results of the study and offer the HFNC
group more oral feeds. However, we found no difference in the
number of oral feeds offered to infants in either group. Another
limitation of our study was the small number of patients,
F4 Glackin SJ, et al. Arch Dis Child Fetal Neonatal Ed 2016;0:F1–F4. doi:10.1136/archdischild-2016-311388
although, the sample size was based on our primary outcome,
we achieved full recruitment and lost no participants to
follow-up.
CONCLUSION
We found no difference in the duration to reach full oral feeds
between stable preterm infants managed on HFNC and those
managed on NCPAP. While there is widespread concern about
oral feeding NCPAP infants, we did not show any difference in
episodes of apnoea, desaturations or bradycardias and we had
no episodes of aspiration in either group. Future studies should
investigate if there is a difference in breast-fed infants between
HFNC and NCPAP managed infants.
Contributors SJG performed literature search, was involved in the study design,
data collection, data analysis, data interpretation and has written first draft of the
manuscript. AO was involved in the study design, staff training prior to the study,
data collection and reviewed final version of the manuscript. SG was involved in the
data collection, data analysis and reviewed final version of the manuscript. JS was
involved in the study design, data collection, data interpretation and reviewed final
version of the manuscript. JM supervised the conduct of the study, was involved in
the study design, data analysis and data interpretation and reviewed final version of
the manuscript.
Competing interests None declared.
Ethics approval Research Ethics Committee, Coombe Women and Infants
University Hospital, reference number 18-2012.
Provenance and peer review Not commissioned; externally peer reviewed.
REFERENCES
1 Kotecha SJ, Adappa R, Gupta N, et al. Safety and efficacy of high-flow nasal
cannula therapy in preterm infants: a meta-analysis. Pediatrics 2015;136:542–53.
2 Manley BJ, Owen LS, Doyle LW, et al. High-flow nasal cannulae in very preterm
infants after extubation. N Engl J Med 2013;369:1425–33.
3 Kubicka ZJ, Limauro J, Darnall RA. Heated, humidified high-flow nasal cannula
therapy: yet another way to deliver continuous positive airway pressure? Pediatrics
2008;121:82–8.
4 Collins CL, Holberton JR, Barfield C, et al. A randomized controlled trial to compare
heated humidified high-flow nasal cannulae with nasal continuous positive airway
pressure postextubation in premature infants. J Pediatr 2013;162:949–54.e1.
5 Kugelman A, Riskin A, Said W, et al. A randomized pilot study comparing heated
humidified high-flow nasal cannulae with NIPPV for RDS. Pediatr Pulmonol
2015;50:576–83.
6 Campbell DM, Shah PS, Shah V, et al. Nasal continuous positive airway pressure
from high flow cannula versus infant flow for preterm infants. J Perinatol
2006;26:546–9.
7 Yoon S-h, Kwon Y-h, Park H-k, et al. High flow nasal cannula versus nasal CPAP in
preterm infants. J Korean Soc Neonatol 2011;18:293–300.
8 Shetty S, Hunt K, Douthwaite A, et al. High-flow nasal cannula oxygen and nasal
continuous positive airway pressure and full oral feeding in infants with
bronchopulmonary dysplasia. Arch Dis Child Fetal Neonatal Ed 2016;101:F408–11.
9 Hanin M, Nuthakki S, Malkar MB, et al. Safety and efficacy of oral feeding in
infants with BPD on nasal CPAP. Dysphagia 2015;30:121–7.
10 Yoder BA, Stoddard RA, Li M, et al. Heated, humidified high-flow nasal cannula
versus nasal CPAP for respiratory support in neonates. Pediatrics 2013;131:e1482–90.
11 Silverman WA, Andersen DH. A controlled clinical trial of effects of water mist on
obstructive respiratory signs, death rate and necropsy findings among premature
infants. Pediatrics 1956;17:1–10.
12 Bell MJ, Ternberg JL, Feigin RD, et al. Neonatal necrotizing enterocolitis.
Therapeutic decisions based upon clinical staging. Ann Surg 1978;187:1–7.
13 Caffrey Osvald E, Prentice P. NICE clinical guideline: antibiotics for the prevention
and treatment of early-onset neonatal infection. Arch Dis Child Educ Pract Ed
2014;99:98–100.