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Review
. 2023 May 5;5(5):CD006405.
doi: 10.1002/14651858.CD006405.pub4.

Nasal high flow therapy for primary respiratory support in preterm infants

Kate A Hodgson  1   2 , Dominic Wilkinson  3   4 , Antonio G De Paoli  5 , Brett J Manley  1   2
Affiliations
Review

Nasal high flow therapy for primary respiratory support in preterm infants

Kate A Hodgson et al. Cochrane Database Syst Rev. .

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 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.

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Conflict of interest statement

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.

Figures

1
1
Study flow diagram.
2
2
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
3
3
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
1.1
1.1. Analysis
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
1.2
1.2. Analysis
Comparison 1: Nasal high flow (nHF) compared with continuous positive airway pressure (CPAP) for primary respiratory support in preterm infants, Outcome 2: Death
1.3
1.3. Analysis
Comparison 1: Nasal high flow (nHF) compared with continuous positive airway pressure (CPAP) for primary respiratory support in preterm infants, Outcome 3: Bronchopulmonary dysplasia
1.4
1.4. Analysis
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
1.5
1.5. Analysis
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
1.6
1.6. Analysis
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
1.7
1.7. Analysis
Comparison 1: Nasal high flow (nHF) compared with continuous positive airway pressure (CPAP) for primary respiratory support in preterm infants, Outcome 7: Duration of any respiratory support (days)
1.8
1.8. Analysis
Comparison 1: Nasal high flow (nHF) compared with continuous positive airway pressure (CPAP) for primary respiratory support in preterm infants, Outcome 8: Duration of supplemental oxygen (days)
1.9
1.9. Analysis
Comparison 1: Nasal high flow (nHF) compared with continuous positive airway pressure (CPAP) for primary respiratory support in preterm infants, Outcome 9: Surfactant treatment
1.10
1.10. Analysis
Comparison 1: Nasal high flow (nHF) compared with continuous positive airway pressure (CPAP) for primary respiratory support in preterm infants, Outcome 10: Duration of hospitalisation (days)
1.11
1.11. Analysis
Comparison 1: Nasal high flow (nHF) compared with continuous positive airway pressure (CPAP) for primary respiratory support in preterm infants, Outcome 11: Pneumothorax
1.12
1.12. Analysis
Comparison 1: Nasal high flow (nHF) compared with continuous positive airway pressure (CPAP) for primary respiratory support in preterm infants, Outcome 12: Nasal trauma
1.13
1.13. Analysis
Comparison 1: Nasal high flow (nHF) compared with continuous positive airway pressure (CPAP) for primary respiratory support in preterm infants, Outcome 13: Nosocomial sepsis
1.14
1.14. Analysis
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
1.15
1.15. Analysis
Comparison 1: Nasal high flow (nHF) compared with continuous positive airway pressure (CPAP) for primary respiratory support in preterm infants, Outcome 15: Time to full feeds (days)
1.16
1.16. Analysis
Comparison 1: Nasal high flow (nHF) compared with continuous positive airway pressure (CPAP) for primary respiratory support in preterm infants, Outcome 16: Retinopathy of prematurity
1.17
1.17. Analysis
Comparison 1: Nasal high flow (nHF) compared with continuous positive airway pressure (CPAP) for primary respiratory support in preterm infants, Outcome 17: Subgroup analysis – mechanical ventilation with or without surfactant permitted
1.18
1.18. Analysis
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
1.19
1.19. Analysis
Comparison 1: Nasal high flow (nHF) compared with continuous positive airway pressure (CPAP) for primary respiratory support in preterm infants, Outcome 19: Subgroup analysis – mechanical ventilation with or without second‐line CPAP permitted
2.1
2.1. Analysis
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
2.2
2.2. Analysis
Comparison 2: Nasal high flow (nHF) compared with nasal intermittent positive pressure ventilation (NIPPV) for primary respiratory support in preterm infants, Outcome 2: Death
2.3
2.3. Analysis
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
2.4
2.4. Analysis
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
2.5
2.5. Analysis
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
2.6
2.6. Analysis
Comparison 2: Nasal high flow (nHF) compared with nasal intermittent positive pressure ventilation (NIPPV) for primary respiratory support in preterm infants, Outcome 6: Mechanical ventilation at any time point after trial entry
2.7
2.7. Analysis
Comparison 2: Nasal high flow (nHF) compared with nasal intermittent positive pressure ventilation (NIPPV) for primary respiratory support in preterm infants, Outcome 7: Surfactant treatment
2.8
2.8. Analysis
Comparison 2: Nasal high flow (nHF) compared with nasal intermittent positive pressure ventilation (NIPPV) for primary respiratory support in preterm infants, Outcome 8: Duration of hospitalisation (days)
2.9
2.9. Analysis
Comparison 2: Nasal high flow (nHF) compared with nasal intermittent positive pressure ventilation (NIPPV) for primary respiratory support in preterm infants, Outcome 9: Pneumothorax
2.10
2.10. Analysis
Comparison 2: Nasal high flow (nHF) compared with nasal intermittent positive pressure ventilation (NIPPV) for primary respiratory support in preterm infants, Outcome 10: Nasal trauma
2.11
2.11. Analysis
Comparison 2: Nasal high flow (nHF) compared with nasal intermittent positive pressure ventilation (NIPPV) for primary respiratory support in preterm infants, Outcome 11: Nosocomial sepsis
2.12
2.12. Analysis
Comparison 2: Nasal high flow (nHF) compared with nasal intermittent positive pressure ventilation (NIPPV) for primary respiratory support in preterm infants, Outcome 12: Gastrointestinal perforation or severe necrotising enterocolitis
2.13
2.13. Analysis
Comparison 2: Nasal high flow (nHF) compared with nasal intermittent positive pressure ventilation (NIPPV) for primary respiratory support in preterm infants, Outcome 13: Time to full feeds (days)
See this image and copyright information in PMC

Update of

References

References to studies included in this review

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References to studies excluded from this review

Akbarian‐Rad 2020 {published data only}
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Hua 2013 {published data only}
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Iranpour 2011 {published and unpublished data}
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Kadivar 2016 {published data only}
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Kang 2016 {published data only}
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Klingenberg 2014 {published data only}
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Lampland 2009 {published data only}
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Lee 2011 {published data only}
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Liu 2014 {published data only}
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Ma 2014 {published data only}
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Manley 2013 {published data only}
    1. Manley BJ, Owen LS, Doyle LW, Andersen CC, Cartwright DW, Pritchard MA, et al. High-flow nasal cannulae in very preterm infants after extubation. New England Journal of Medicine 2013;369(15):1425-33. [DOI: 10.1056/NEJMoa1300071] [PMID: ] - DOI - PubMed
Miller 2010 {published data only}
    1. Miller SM, Dowd SA. High-flow nasal cannula and extubation success in the premature infant: a comparison of two modalities. Journal of Perinatology 2010;30(12):805-8. [DOI: 10.1038/jp.2010.38] [PMID: ] - DOI - PubMed
Mostafa‐Gharehbaghi 2015 {published data only}
    1. Mostafa-Gharehbaghi M, Mojabi H. Comparing the effectiveness of nasal continuous positive airway pressure (NCPAP) and high flow nasal cannula (HFNC) in prevention of post extubation assisted ventilation. Zahedan Journal of Research in Medical Sciences 2015;17(6):e984. [DOI: 10.17795/zjrms984] - DOI
Nasef 2015 {published data only}
    1. Nasef N, El-Gouhary E, Schurr P, Reilly M, Beck J, Dunn M, et al. High-flow nasal cannulae are associated with increased diaphragm activation compared with nasal continuous positive airway pressure in preterm infants. Acta Paediatrica 2015;104(8):e337-43. [DOI: 10.1111/apa.12998] [PMID: ] - DOI - PubMed
Pyon 2008 {published data only}
    1. Pyon KH, Aghai ZH, Nakhla TA, Stahl GE, Saslow JG. High flow nasal cannula in preterm infants: effects of high flow rates on work of breathing. In: Proceedings of the Pediatric Academic Societies Annual Meeting; 2008 May 3-6; Honolulu (HI). 2008:E-PAS2008:633763.13.
Saslow 2006 {published data only}
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Shokouhi 2019 {published data only}
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Soonsawad 2016 {published data only}
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References to studies awaiting assessment

Awad 2021 {published data only}
    1. Awad HA, El-Farrash RA, Shinkar DM, Aly YA, Soliman N, Alhassanin AH. A study of heated, humidified high flow nasal cannula as an initial respiratory support in preterm neonates. QJM : An International Journal of Medicine 2021;114:Suppl 1.
Balasubramanian 2022 {published data only}
    1. Balasubramanian H, Sakharkar S, Majarikar S, Srinivasan L, Kabra NS, Garg B, et al. Efficacy and safety of two different flow rates of nasal high-flow therapy in preterm neonates ≥28 weeks of gestation: a randomized controlled trial. American Journal of Perinatology 2022;39(15):1693-701. - PubMed
Cetinkaya 2018 {published data only (unpublished sought but not used)}
    1. Cetinkaya M, Cebeci B, Semerci S Y, Kurnaz D, Saglam O. Comparison of three different non-invasive ventilation modes in preterm infants with respiratory distress syndrome: prospective randomized study. 26th European Workshop on Neonatology; 2018 Sep 2–5; Cappadocia, Turkey. [content.iospress.com/download/journal-of-neonatal-perinatal-medicine/npm...
Febre 2015 {published data only}
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Lawrence 2012 {published data only}
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Oktem 2021 {published data only}
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Shirvani 2019 {published data only}
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References to ongoing studies

ACTRN12610000677000 {published data only}
    1. ACTRN12610000677000. High flow support versus continuous positive airway pressure (CPAP) support in non-acute respiratory support for preterm infants from 30 weeks corrected gestation. who.int/trialsearch/Trial2.aspx?TrialID=ACTRN12610000677000 (first received 18 August 2010).
ACTRN12611000233921 {published data only}
    1. ACTRN12611000233921. The use of headbox oxygen versus high flow nasal cannula (HFNC) for neonatal respiratory distress in non-tertiary hospitals [High-flow nasal cannulae versus ambient oxygen for the treatment of newborn infants with early respiratory distress in non-tertiary special care nurseries – a multicentre randomised controlled trial]. anzctr.org.au/Trial/Registration/TrialReview.aspx?id=336574 (first received 21 February 2011).
CTRI/2017/09/009910 {published data only}
    1. CTRI/2017/09/009910. High flow nasal cannulae versus nasal continuous positive airway pressure in neonates with respiratory distress syndrome [To study the equivalence of high flow nasal cannula oxygen therapy and nasal continuous positive airway pressure as respiratory support in preterm neonates – a prospective observational study]. ctri.nic.in/Clinicaltrials/pdf_generate.php?trialid=13233&EncHid=&am... (first received 25 September 2017).
CTRI/2019/10/021633 {published data only}
    1. CTRI/2019/10/021633. Breathing stabilization in small babies at the time of birth [Delivery room respiratory stabilization of preterm neonates: a randomized controlled trial]. ctri.nic.in/Clinicaltrials/pdf_generate.php?trialid=37352&EncHid=&am... (first received 14 October 2019).
Irct2016052510026N {published data only}
    1. Irct2016052510026N. Therapeutic effect of heated, humidified, high-flow nasal cannula (HHHFNC) in respiratory distress syndrome. trialsearch.who.int/Trial2.aspx?TrialID=IRCT2016052510026N7 (first received 31 March 2019). [CENTRAL: CN-01895122]
Irct20180226038865N {published data only}
    1. Irct20180226038865N. Comparison of two forms of non-invasive respiratory supporting preterm infants. trialsearch.who.int/Trial2.aspx?TrialID=IRCT20180226038865N1 (first received 31 March 2019). [CENTRAL: CN-01895352]
Irct20190623043988N {published data only}
    1. Continuous positive airway pressure or high flow nasal cannula for respiratory distress syndrome. trialsearch.who.int/Trial2.aspx?TrialID=IRCT20190623043988N1 (first received 5 July 2019).
Irct20200616047788N {published data only}
    1. Irct20200616047788N. Comparing two respiratory support methods in RDS treatment of premature neonates. trialsearch.who.int/Trial2.aspx?TrialID=IRCT20200616047788N1 (first received 21 July 2020).
ISRCTN66716753 {published data only}
    1. ISRCTN66716753. High flow nasal prongs (HFNP) therapy versus nasal continuous positive airway pressure (NCPAP) in establishing full oral feeds in very low birth weight (VLBW) infants – randomized controlled trial [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?]. isrctn.com/ISRCTN66716753 (first received 1 February 2013).
NCT01270581 {unpublished data only}
    1. NCT01270581. High flow nasal cannula versus bubble nasal CPAP for the treatment of transient tachypnea of the newborn in infants ≥ 35 weeks gestation. clinicaltrials.gov/ct2/show/NCT01270581 (first received 5 January 2011).
NCT02055339 {published data only}
    1. NCT02055339. Comparison of nasal continuous positive airway pressure with low flow oxygen versus heated, humidified high flow nasal cannula for oral feeding of the premature infant (chomp trial): a pilot study [Pilot study comparing different modes of non-invasive ventilation for the oral feeding of preterm infants (CHOMP)]. clinicaltrials.gov/ct2/show/NCT02055339 (first received 5 February 2014).
NCT02499744 {published data only}
    1. NCT02499744. Humidified high flow nasal cannula versus nasal intermittent positive ventilation in neonates. clinicaltrials.gov/ct2/show/NCT02499744 (first received 16 July 2015).
UMIN000018983 {published data only}
    1. UMIN000018983. Effective and safe use of heated humidified high flow nasal cannula in neonates. umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000021932 (first received 29 September 2015).

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References to other published versions of this review

Wilkinson 2007
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Publication types