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.
- Continuous Positive Airway Pressure
- Preterm Infant
- Enteral Nutrition
- High Flow Nasal Cannula
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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.
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 published 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 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 difficulty 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 significant 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 potential 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 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 gestation. 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 supplemental 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 significant congenital, respiratory, cardiac or airway abnormalities or infants who were still on patient-assist NCPAP (added pressure 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 settings (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 administered 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 generated 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 sequentially 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 episodes 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 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 duration 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 gestational age at birth, birth weight, Apgar scores, antenatal steroids, 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 arteriosus 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 retrospective 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 analysed 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.
There were 149 VLBW infants born at <30 weeks of gestation, who had survived to 32 weeks of gestation during the recruitment period (January 2013 to December 2014). Of those, 59 infants were eligible for randomisation and 44 infants were randomised to the trial (figure 1). There were no statistical differences between the NCPAP group and HFNC group in relation to the patient characteristics at enrolment (table 1).
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.
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 bronchopulmonary 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 analysis, 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 about aspiration, which may have led to some infants missing their opportunity to learn how to feed and developing oral aversion. Their NCPAP group were also of earlier gestation and lower birth weight, and therefore represented a different population to the HFNC group.
Our results are supported by an RCT which included duration to reach full oral feeds in their secondary outcomes and found no difference in these results between the HFNC group and the 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 population 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 successfully. 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 assignment. 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, although, the sample size was based on our primary outcome, we achieved full recruitment and lost no participants to follow-up.
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.