High‐flow nasal cannulae for respiratory support in adult intensive care patients

Sharon R Lewis; Philip E Baker; Roses Parker; Andrew F Smith

doi:10.1002/14651858.CD010172.pub2

Cochrane Database of Systematic Reviews

Cánulas nasales de alto flujo para la asistencia respiratoria de pacientes adultos en cuidados intensivos

Información

DOI:

https://doi.org/10.1002/14651858.CD010172.pub2 Copiar DOI

Base de datos:

Cochrane Database of Systematic Reviews

Versión publicada:

30 mayo 2017see what's new

Tipo:

Intervention

Etapa:

Review

Grupo Editorial Cochrane:

Grupo Cochrane de Atención crítica y de emergencia

Copyright:

Copyright © 2017 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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Autores

Sharon R Lewis

Correspondencia a: Lancaster Patient Safety Research Unit, Royal Lancaster Infirmary, Lancaster, UK

[email protected]
Philip E Baker

Academic Centre, Oxford University Hospitals NHS Trust, Oxford, UK
Roses Parker

Cochrane MOSS Network, c/o Cochrane Pain Palliative and Supportive Care Group, Oxford University Hospitals NHS Foundation Trust, Oxford, UK
Andrew F Smith

Department of Anaesthesia, Royal Lancaster Infirmary, Lancaster, UK

Contributions of authors

Contributions made by authors in the previous version of the review can be found in Corley 2017.

Sharon R Lewis (SRL), Philip E Baker (PEB), Roses Parker (RP), Andrew F Smith (AFS).

Co‐ordinating the review update, undertaking manual searches, organizing retrieval of papers, screening retrieved papers against inclusion criteria, extracting data from papers, conducting 'Risk of bias' assessments, entering data in RevMan Web 2019, analysing and interpreting data: PEB and SRL

Writing the review: PEB, RP and SRL

Contacting study authors for additional information: PEB

Taking responsibility for reading and checking the review before submission: PEB, SRL, RP, AFS.

Declarations of interest

Sharon R Lewis (SRL), Philip E Baker (PEB), Roses Parker (RP), Andrew F Smith (AFS).

Review authors SRL, PEB, RP and AFS have no conflicts of interest to declare.

Acknowledgements

We would like to thank Jasmin Arrich (Content Editor); Nathan Pace (Statistical Editor); Kevin Dysart and Ravi Tiruvoipati (Peer Reviewers); Stella O'Brien (Consumer Referee); Janne Vendt (Information Specialist); Liz Bickerdike (Network Associate Editor, Acute and Emergency Care Network); Teo Quay and Vernon Hedge (Managing Editors); and Harald Herkner (Co‐ordinating Editor) for their help and editorial advice during the preparation of the present update of this systematic review.

We would like to thank the previous review authors (Amanda Corley, Claire M Rickard, Leanne M Aitken, Amy Johnston, Adrian Barnett, and John F Fraser) for their contribution to the protocol and the earlier version of this review (Corley 2017).

We would like to thank Harald Herkner (Content Editor); Cathal Walsh (Statistical Editor); Georgina Imberger, Kevin Dysart, Ravi Tiruvoipati, and Samir Jaber (Peer Reviewers), and Shunjie Chua (Consumer Referee) for help and editorial advice provided during preparation of the earlier version of this review (Corley 2017).

We would also like to thank Karen Hovhannisyan (Former Trials Search Co‐ordinator for the Cochrane Anaesthesia, Critical and Emergency Care (ACE) Group) for developing the search strategy, Jane Cracknell (Managing Editor, ACE) for assisting with protocol and review development; and Joan Webster for providing additional advice on the analytical approach for the earlier version of this review (Corley 2017).

Version history

Published

Title

Stage

Authors

Version

2021 Mar 04

High‐flow nasal cannulae for respiratory support in adult intensive care patients

Review

Sharon R Lewis, Philip E Baker, Roses Parker, Andrew F Smith

https://doi.org/10.1002/14651858.CD010172.pub3

2017 May 30

High‐flow nasal cannulae for respiratory support in adult intensive care patients

Review

Sharon R Lewis, Philip E Baker, Roses Parker, Andrew F Smith

https://doi.org/10.1002/14651858.CD010172.pub2

2012 Nov 14

High flow nasal cannulae for respiratory support in adult intensive care patients

Protocol

Amanda Corley, Claire M Rickard, Leanne M Aitken, Amy Johnston, Adrian Barnett, John F Fraser

https://doi.org/10.1002/14651858.CD010172

Differences between protocol and review

Changes between protocol and review made in the previous publication are reported in Corley 2017.

Differences between the current and previous version of the review

We made the following changes to Corley 2017.

Authors: we added two new authors to the review team (Philip Baker and Roses Parker) and we removed six authors from the review team who were no longer able to contribute to the review owing to time constraints: Amanda Corley, Claire M Rickard, Leanne M Aitken, Amy Johnston, Adrian Barnett, John F Fraser.
Objectives: we re‐worded the review objectives, using a single sentence, following current Cochrane guidance.
Types of studies: we excluded cluster‐ and quasi‐randomized studies. Quasi‐randomized studies were originally included as it was expected that limited data would be available for this review. However, as sufficient high‐quality studies are now published for this topic, we believed that it was appropriate to exclude both these study designs from this update.
Types of interventions: we made a greater distinction between the different types of respiratory support in the review. We separated the interventions into two comparison groups (standard oxygen therapy; and NIV or NIPPV). We made edits to other sections of the text in order to specify the separate management of these two comparison groups. For consistency, we used the term 'standard oxygen therapy' throughout the review to refer to low‐flow oxygen, conventional oxygen therapy and standard oxygen therapy; we had previously used these terms interchangeably throughout the review. We clarified that we included standard oxygen therapy with or without humidification and heating.
Types of outcomes: we removed the term 'primary outcome', instead splitting the outcomes into 'important' and 'additional' outcomes, where the 'important outcomes' appear in the 'Summary of findings' tables. For the outcome 'treatment failure', we clarified that this was escalation of respiratory support that included NIV, as well as NIPPV or invasive ventilation depending on the initial respiratory therapy. For the outcome 'adverse events', we specified and collected data only on specific outcomes. We found that study authors varied in whether or not they defined outcomes as 'adverse events'. We, therefore, collected data on: respiratory infections (pneumonia, and tracheobronchitis), abdominal distension, and nasal mucosa or skin trauma. Data for other adverse events that were previously reported can be found in Corley 2017. We also clarified in this section, that we separated data for respiratory effects and participant‐reported outcomes according to short‐term and longer‐term effects. We removed PCO₂ as an outcome; this is a predictor of PaCO₂ which is commonly reported in studies.
Search methods: we updated the search strategies following the advice and support of the Information Specialist for the Cochrane Emergency and Critical Care Group. In this review update, we did not separately search for abstracts from conference proceedings (for the European Society of Intensive Care Medicine, the Australia and New Zealand Intensive Care Society, the Society of Critical Care Medicine, and the American Thoracic Society); we expected that publications from these conference proceedings would be included in the comprehensive database search strategies.
Data extraction and management: we edited the data extraction forms, in order to use a template that was more consistent with the tables in Characteristics of included studies. In addition, we added detail about the information collected during data extraction.
Measures of treatment effect: when dealing with continuous data presented on different scales, we added that we would aim to scale and invert the outcome data to allow calculation of a mean difference before calculating standardized mean difference.
Assessment of risk of bias: we reduced the text in this section. Rather than making 'Risk of bias' judgements on all studies, we only made judgements on studies for which we reported outcome data; we specified this in this Methods section. We made judgements separately for detection bias according to whether outcomes were subjective (participant‐reported) or objective (all other outcomes).
Sensitivity analysis: we provided additional clarity to the sensitivity analyses. We added sensitivity analysis to explore the effects of high risk of bias in domains other than selection bias (as we performed a separate sensitivity analysis for this domain). In addition, we performed further sensitivity analyses to exclude studies that were commercially funded with a potential conflict of interest on advice from the Cochrane Emergency and Critical Care Group editorial team. We also used sensitivity analysis on all of the outcomes in the 'Summary of findings' tables, because we used this information when assessing the certainty of the evidence with GRADE.
Summary of findings: we conducted GRADE assessments for the two comparison groups introduced in this latest update.

Notes

We would like to thank Harald Herkner (Content Editor); Cathal Walsh (Statistical Editor); and Georgine Imberger, Jean‐Damien Ricard, and Kevin Dysart (Peer Reviewers) for help and editorial advice provided during preparation of the protocol (Corley 2012) for this systematic review.

Keywords

MeSH

Medical Subject Headings (MeSH) Keywords

Medical Subject Headings Check Words

Adult; Humans;

PICO

Population

Intervention

Comparison

Outcome

El uso y la enseñanza del modelo PICO están muy extendidos en el ámbito de la atención sanitaria basada en la evidencia para formular preguntas y estrategias de búsqueda y para caracterizar estudios o metanálisis clínicos. PICO son las siglas en inglés de cuatro posibles componentes de una pregunta de investigación: paciente, población o problema; intervención; comparación; desenlace (outcome).

Para saber más sobre el uso del modelo PICO, puede consultar el Manual Cochrane.

Figure 1

Flow diagram. Search conducted in April 2020

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Figure 2

Risk of bias summary: review authors' judgements about each risk of bias item for each included study. We only conducted 'Risk of bias' assessments in studies for which we reported outcome data, and for domains that were relevant to reported outcomes (in particular, for detection bias of objective and subjective measures); blank spaces, therefore, indicate that 'Risk of bias' assessment was not conducted for the outcome, or for a particular domain.

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Figure 3

Funnel plot for outcome 1.1 Treatment failure.

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Figure 4

Funnel plot for outcome 1.2 In‐hospital mortality

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Analysis 1.1

Comparison 1: HFNC versus standard oxygen therapy, Outcome 1: Treatment failure (escalation of respiratory support to NIV, NIPPV or invasive ventilation)

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Analysis 1.2

Comparison 1: HFNC versus standard oxygen therapy, Outcome 2: In‐hospital mortality

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Analysis 1.3

Comparison 1: HFNC versus standard oxygen therapy, Outcome 3: Important adverse events

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Analysis 1.4

Comparison 1: HFNC versus standard oxygen therapy, Outcome 4: Length of ICU stay (days)

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Comparison 1: HFNC versus standard oxygen therapy, Outcome 5: Short‐term respiratory effects: PaO 2/FiO 2 (mmHg)

Analysis 1.5

Comparison 1: HFNC versus standard oxygen therapy, Outcome 5: Short‐term respiratory effects: PaO ₂/FiO ₂ (mmHg)

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Analysis 1.6

Comparison 1: HFNC versus standard oxygen therapy, Outcome 6: Comfort

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Comparison 1: HFNC versus standard oxygen therapy, Outcome 7: Long‐term respiratory effects: PaO 2/FiO 2 (mmHg)

Analysis 1.7

Comparison 1: HFNC versus standard oxygen therapy, Outcome 7: Long‐term respiratory effects: PaO ₂/FiO ₂ (mmHg)

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Comparison 1: HFNC versus standard oxygen therapy, Outcome 8: Short‐term and long‐term respiratory effects: PaO 2 (mmHg)

Analysis 1.8

Comparison 1: HFNC versus standard oxygen therapy, Outcome 8: Short‐term and long‐term respiratory effects: PaO ₂ (mmHg)

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Comparison 1: HFNC versus standard oxygen therapy, Outcome 9: Short‐term and long‐term respiratory effects: SpO 2 (%)

Analysis 1.9

Comparison 1: HFNC versus standard oxygen therapy, Outcome 9: Short‐term and long‐term respiratory effects: SpO ₂ (%)

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Comparison 1: HFNC versus standard oxygen therapy, Outcome 10: Short‐term respiratory effects: PaCO 2 (mmHg)

Analysis 1.10

Comparison 1: HFNC versus standard oxygen therapy, Outcome 10: Short‐term respiratory effects: PaCO ₂ (mmHg)

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Analysis 1.11

Comparison 1: HFNC versus standard oxygen therapy, Outcome 11: Short‐term and long‐term respiratory rate (breaths/min)

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Analysis 1.12

Comparison 1: HFNC versus standard oxygen therapy, Outcome 12: Length of hospital stay (days)

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Analysis 1.13

Comparison 1: HFNC versus standard oxygen therapy, Outcome 13: Refusal to continue with treatment

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Analysis 2.1

Comparison 2: HFNC versus NIPPV or NIV, Outcome 1: Treatment failure (escalation of respiratory support to NIV, NIPPV or invasive ventilation)

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Analysis 2.2

Comparison 2: HFNC versus NIPPV or NIV, Outcome 2: In‐hospital mortality

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Analysis 2.3

Comparison 2: HFNC versus NIPPV or NIV, Outcome 3: Important adverse events: pneumonia

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Comparison 2: HFNC versus NIPPV or NIV, Outcome 4: Short‐term respiratory effects: PaO 2/FiO 2 (mmHg)

Analysis 2.4

Comparison 2: HFNC versus NIPPV or NIV, Outcome 4: Short‐term respiratory effects: PaO ₂/FiO ₂ (mmHg)

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Analysis 2.5

Comparison 2: HFNC versus NIPPV or NIV, Outcome 5: Length of ICU stay (days)

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Analysis 2.6

Comparison 2: HFNC versus NIPPV or NIV, Outcome 6: Short‐term comfort (continuous data)

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Analysis 2.7

Comparison 2: HFNC versus NIPPV or NIV, Outcome 7: Duration of respiratory support (hours)

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Comparison 2: HFNC versus NIPPV or NIV, Outcome 8: Long‐term respiratory effects: PaO 2/FiO 2 (mmHg)

Analysis 2.8

Comparison 2: HFNC versus NIPPV or NIV, Outcome 8: Long‐term respiratory effects: PaO ₂/FiO ₂ (mmHg)

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Comparison 2: HFNC versus NIPPV or NIV, Outcome 9: Short‐term respiratory effects: PaO 2 (mmHg)

Analysis 2.9

Comparison 2: HFNC versus NIPPV or NIV, Outcome 9: Short‐term respiratory effects: PaO ₂ (mmHg)

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Comparison 2: HFNC versus NIPPV or NIV, Outcome 10: Short‐term and long‐term respiratory effects: PaCO 2 (mmHg)

Analysis 2.10

Comparison 2: HFNC versus NIPPV or NIV, Outcome 10: Short‐term and long‐term respiratory effects: PaCO ₂ (mmHg)

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Analysis 2.11

Comparison 2: HFNC versus NIPPV or NIV, Outcome 11: Short‐term respiratory effects: breaths/min

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Analysis 2.12

Comparison 2: HFNC versus NIPPV or NIV, Outcome 12: Dyspnoea (any improvement)

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Summary of findings 1. HFNC compared to standard oxygen therapy for respiratory support in adult intensive care patients

Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	Number of participants (studies)	Certainty of the evidence (GRADE)	Comments
High‐flow nasal cannulae compared to standard oxygen therapy for respiratory support in adult intensive care patients
Population: adults in the ICU, requiring respiratory support Setting: ICUs. In this review, these ICUs were in: Australia; Belgium; China; France; Italy; New Zealand; Spain; Taiwan; Thailand; UK. Intervention: oxygen delivered via HFNC, initiated after extubation from invasive mechanical ventilation or without prior use of invasive mechanical ventilation Comparison: standard oxygen therapy delivered via nasal cannula or face mask
Outcomes	Risk with standard oxygen therapy	Risk with HFNC	Relative effect (95% CI)	Number of participants (studies)	Certainty of the evidence (GRADE)	Comments
Treatment failure (escalation of respiratory therapy to NIV, NIPPV or invasive ventilation) Measured up to 28 days	Study population		RR 0.62 (0.45 to 0.86)	3044 (15 studies)	⊕⊕⊝⊝ Low^a
	261 per 1000	162 per 1000 (117 to 224)	RR 0.62 (0.45 to 0.86)	3044 (15 studies)	⊕⊕⊝⊝ Low^a
In‐hospital mortality (up to 90 days; included studies reported in‐hospital mortality, and mortality up to 28 days, up to ICU discharge, and at unspecified time points)	Study population		RR 0.96 (0.82 to 1.11)	2673 (11 studies)	⊕⊕⊕⊝ Moderate^b	‐
	163 per 1000	156 per 1000 (134 to 181)	RR 0.96 (0.82 to 1.11)	2673 (11 studies)	⊕⊕⊕⊝ Moderate^b	‐
Adverse events Respiratory infection (pneumonia) Nasal mucosa or skin trauma	Study population for pneumonia		RR 0.72 (0.48 to 1.09)	1057 (4 studies)	⊕⊕⊕⊝ Moderate^c	‐ ‐
	84 per 1000	61 per 1000 (40 to 92)	RR 0.72 (0.48 to 1.09)	1057 (4 studies)	⊕⊕⊕⊝ Moderate^c
	Study population for nasal mucosa or skin trauma		RR 3.66 (0.43 to 31.48)	617 (2 studies)	⊕⊝⊝⊝ Verylow^d
	3 per 1000	12 per 1000 (1 to 103)	RR 3.66 (0.43 to 31.48)	617 (2 studies)	⊕⊝⊝⊝ Verylow^d
Length of ICU stay	1.88 days	MD 0.12 days higher (0.03 days lower to 0.27 days higher)	‐	1014 (7 studies)	⊕⊕⊝⊝ Low^e	In addition, 5 studies reported median lengths of ICU stay which we did not combine in analysis; these studies all reported little or no difference in median lengths of ICU stay
Respiratory effects: PaO₂/FiO₂ ratio up to 24 hours after initiation of therapy	188.5 mmHg	MD 10.34 mmHg higher (17.31 mmHg lower to 38 mmHg higher)	‐	600 (5 studies)	⊕⊝⊝⊝ Verylow^f	In addition, 1 study reported median values which we did not combine in analysis; this study reported higher PaO₂/FiO₂ when HFNC was used
Comfort (short‐term effect) Measured up to 24 hours, scales were standardised to allow comparison; higher numbers indicate more comfort	6.81	MD 0.31 higher (0.61 lower to 1.22 higher)	‐	662 (4 studies)	⊕⊝⊝⊝ Verylow^g	In addition, 2 studies reported median values which we did not combine in analysis; 1 of these studies reported little or no difference in comfort according to type of respiratory support used, and 1 study reported improved comfort when HFNC was used
Comfort (long‐term effect) Measured at more than 24 hours, scales were standardized to allow comparison; higher numbers indicate more comfort	7.10	MD 0.59 higher (2.29 lower to 3.47 higher)	‐	445 (2 studies)	⊕⊝⊝⊝ Verylow^g	In addition, 1 study reported data in a figure and we did not combine these data in analysis; this study reported little or no difference in comfort according to the type of respiratory support used
*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). For length of stay, PaO₂/FiO₂ and comfort, we present baseline risk values for standard oxygen therapy as the weighted mean values reported in included studies for each outcome. For comfort, these values are scores on a scale from 0 (least comfort) to 10 (most comfort). CI: confidence interval; HFNC: high‐flow nasal cannulae; ICU: intensive care unit; MD: mean difference; PaO₂/FiO₂: ratio of partial pressure of arterial oxygen to the fraction of inspired oxygen; RR: risk ratio; SMD: standardized mean difference
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
^aWe downgraded by one level for inconsistency because we noted a moderate level of statistical heterogeneity; we also noted more variation in the data from studies in which respiratory support was given post‐extubation which we could not explain. We also downgraded by one level for study limitations because we judged some studies to have an unclear risk of selection bias; excluding these studies in sensitivity analysis no longer indicated an improvement with HFNC use. ^bWe downgraded by one level for inconsistency because we noted inconsistencies in the data which we expected were caused by the differences in illness severity of participants in the studies which is likely to impact on mortality rates between studies. ^cWe downgraded by one level for imprecision because only four studies contributed evidence for this outcome. ^dWe downgraded by three levels: we downgraded two levels for imprecision because only two studies contributed evidence, of which only one reported events. We also downgraded by one level for study limitations because this study did not report study trials registration and we could not be certain whether it was at risk of selective reporting bias. ^eWe downgraded by two levels: we downgraded by one level for inconsistency because we noted variation in the lengths of stay between studies which we expected was because of different illness severity between study participants. We also downgraded by one level for study limitations because we noted some high risks of bias in some included studies. ^fWe downgraded by three levels: we downgraded by two levels for inconsistency because we noted a substantial amount of statistical heterogeneity which we could not explain, and we downgraded by one level for study limitations because we noted differences in the effect estimate when we excluded studies at unclear or high risks of selection bias in sensitivity analyses. ^gWe downgraded by three levels: we downgraded by two levels for inconsistency because we noted a substantial level of statistical heterogeneity and variation in the data between the studies which we could not explain. We also downgraded by one level for imprecision because few studies contributed data for this outcome.

Summary of findings 1. HFNC compared to standard oxygen therapy for respiratory support in adult intensive care patients

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Summary of findings 2. HFNC compared to NIPPV or NIV for respiratory support in adult intensive care patients

Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	Number of participants (studies)	Certainty of the evidence (GRADE)	Comments
High‐flow nasal cannulae compared to NIPPV or NIV for respiratory support in adult intensive care patients
Population: adults in the ICU, requiring respiratory support Setting: ICUs. In this review, these ICUs were in: Belgium, China, France, Saudi Arabia, and Spain Intervention: oxygen delivered via HFNC, initiated after extubation from invasive mechanical ventilation or without prior use of invasive mechanical ventilation Comparison: oxygen delivered via NIV or NIPPV (using BiPAP)
Outcomes	Risk with NIPPV or NIV	Risk with HFNC	Relative effect (95% CI)	Number of participants (studies)	Certainty of the evidence (GRADE)	Comments
Treatment failure (escalation of respiratory therapy to NIV, NIPPV or invasive ventilation) Measured up to 28 days	Study population		RR 0.98 (0.78 to 1.22)	1758 (5 studies)	⊕⊕⊝⊝ Low^a	We conducted subgroup analysis and found no evidence of a difference in treatment failure when used post‐extubation (RR 1.12, 95% CI 0.89 to 1.41; 3 studies, 1472 participants) and without prior use of mechanical ventilation (RR 0.77, 95% CI 0.58 to 1.03; 2 studies, 286 participants)
	202 per 1000	198 per 1000 (158 to 247)	RR 0.98 (0.78 to 1.22)	1758 (5 studies)	⊕⊕⊝⊝ Low^a
In‐hospital mortality (up to 90 days; included studies reported in‐hospital mortality, and mortality up to 28 days and up to ICU discharge)	Study population		RR 0.92 (0.64 to 1.31)	1758 (5 studies)	⊕⊕⊝⊝ Low^a	‐
	136 per 1000	126 per 1000 (87 to 179)	RR 0.92 (0.64 to 1.31)	1758 (5 studies)	⊕⊕⊝⊝ Low^a	‐
Adverse events Respiratory infection (pneumonia)	Study population for pneumonia		RR 0.51 (0.17 to 1.52)	1750 (3 studies)	⊕⊝⊝⊝ Verylow^b	‐
Adverse events Respiratory infection (pneumonia)	159 per 1000	81 per 1000 (27 to 241)	RR 0.51 (0.17 to 1.52)	1750 (3 studies)	⊕⊝⊝⊝ Verylow^b	‐
Barotrauma (pneumothorax)	Study population for barotrauma		RR 1.15 (0.42 to 3.14)	830 (1 study)	⊕⊝⊝⊝ Low^c	‐
Barotrauma (pneumothorax)	17 per 1000	19 per 1000 (7 to 53)	RR 1.15 (0.42 to 3.14)	830 (1 study)	⊕⊝⊝⊝ Low^c	‐
Nasal mucosa or skin trauma	Study population for nasal mucosa or skin trauma		‐	‐	‐	No studies reported this outcome
Nasal mucosa or skin trauma	‐	‐	‐	‐	‐	No studies reported this outcome
Length of ICU stay	9.9 days	MD 0.72 days lower (2.85 days lower to 1.42 days higher)	‐	246 (2 studies)	⊕⊕⊝⊝ Low^d	In addition, 2 studies reported median lengths of ICU stay which we did not combine in analysis; these studies reported little or no difference in median lengths of ICU stay
Respiratory effects: PaO₂/FiO₂ ratio up to 24 hours after initiation of therapy	228.9 mmHg	MD 58.1 mmHg lower (71.68 mmHg lower to 44.51 mmHg lower)	‐	1086 (3 studies)	⊕⊕⊝⊝ Low^e	‐
Comfort (short‐term effect) Measured up to 24 hours, scales were standardized to allow comparison; higher numbers indicate more comfort	6.06	MD 1.33 higher (0.74 higher to 1.92 higher)	‐	258 (2 studies)	⊕⊝⊝⊝ Verylow^f	In addition, 1 study reported improved comfort with HFNC (RR 1.30, 95% CI 1.10 to 1.53; 1 study, 168 participants), and 1 study (830 participants) reported little or no difference between types of respiratory support, with comfort rated as 'poor', 'acceptable' or 'good'.
Comfort (long‐term effect) Measured at more than 24 hours	‐	‐	‐	‐	⊕⊝⊝⊝ Verylow^g	1 study (304 participants) reported little or no difference between types of respiratory support, with comfort rated as 'poor', 'acceptable' or 'good'.
*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). We present baseline risk values for NIPPV/NIV as the weighted mean values reported in included studies for each outcome. For comfort, these values are a score from 0 (least comfort) to 10 (most comfort). CI: Confidence interval; HFNC: high‐flow nasal cannulae; ICU: intensive care unit; MD: mean difference; NIPPV: non‐invasive positive pressure ventilation; NIV: non‐invasive ventilation; PaO₂/FiO₂: ratio of partial pressure of arterial oxygen to the fraction of inspired oxygen; RR: risk ratio; SMD: standardized mean difference
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
^aWe downgraded by two levels: we downgraded by one level for inconsistency because we noted some variation in the results which we could not explain. We also downgraded by one level for study limitations because we judged one study to have a high risk of bias owing to the use of alternative treatment between intermittent HFNC use. ^bWe downgraded by three levels: we downgraded by two levels for inconsistency because we noted variation in the results of individual studies and a substantial level of statistical heterogeneity, and by one level for study limitations because we judged one study to have a high risk of bias owing to the use of alternative treatment between intermittent HFNC use. ^cWe downgraded by two levels for imprecision because only one study contributed evidence to this outcome and we noted a wide CI in the effect. ^dWe downgraded by two levels: we downgraded by one level for inconsistency because we noted a wide variation in length of stay within studies, and by one level for study limitations because we judged one study to have a high risk of bias owing to the use of alternative treatment between intermittent HFNC use. ^eWe downgraded by two levels: we downgraded by one level for inconsistency because one study had a particularly wide CI and we noted differences in PaO₂/FiO₂ between studies which could be explained by the different reasons for needing respiratory support between studies. We also downgraded by one level for study limitations because we judged one study to have a high risk of bias owing to the use of alternative treatment between intermittent HFNC use. ^fWe downgraded by three levels: we downgraded by two levels for inconsistency because we noted some variation between study results, and by one level for study limitations because we judged one study to have a high risk of bias owing to the use of alternative treatment between intermittent HFNC use. ^gWe downgraded by three levels: we downgraded by two levels for imprecision because only one study contributed evidence for this outcome, and one level for study limitations because we noted a high rate of attrition for comfort scores measured at day 3.

Summary of findings 2. HFNC compared to NIPPV or NIV for respiratory support in adult intensive care patients

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Table 1. Comparison 1 (HFNC vs standard oxygen therapy): continuous outcomes from single studies

Important outcomes	HFNC	Standard oxygen therapy	Effect estimate^a	P values^b	Study ID
Length of ICU stay (days)	Median (IQR): 8 (4 to 14)	Median (IQR): 6 (4 to 13)		0.07	Azoulay 2018
Length of ICU stay (days)	Median (IQR): 6 (4 to 16)	Median (IQR): 5 (3 to 13)		0.53	Futier 2016
Length of ICU stay (days)	Median (IQR): 6 (2 to 8)	Median (IQR): 6 (2 to 9)		Not reported	Hernandez 2016b
Length of ICU stay (days)	Median (IQR): 10 (7 to 13)	Median (IQR): 9 (6 to 12)		0.453	Hu 2020
Length of ICU stay (days)	Median (IQR): 1 (1 to 2)	Median (IQR): 1 (1 to 2)		0.949	Zochios 2018
Short‐term oxygenation (PaO₂/FiO₂)	Median (IQR):150 (104 to 230)	Median (IQR):119 (86 to 165)		P value not reported. Study authors described difference as significantly higher in the HFNC group	Azoulay 2018
Short‐term comfort (at 120 minutes) Scale of 0 to 10 (0 = absence of discomfort, 10 = worst possible discomfort)	Median (IQR): 3 (1 to 5)	Median (IQR): 3 (0 to 5)		0.88	Lemiale 2015
Long‐term comfort (at 24 hours) Scale of 0 to 10 (0 = no discomfort, 10 = maximum discomfort)	Median (IQR): 3 (3 to 4.5)	Median (IQR): 7 (6 to 8)		< 0.001	Song 2017
Additional outcomes	HFNC	Standard oxygen therapy	Effect estimate^a	P values^b	Study ID
Duration of respiratory support (hours)	Mean (SD): 59.0 (± 30.8)	Mean (SD): 65.0 (± 41.6)	MD (95% CI) ‐6.00 (‐13.77 to 1.77)	0.13	Parke 2013a
Atelectasis (radiological atelectasis score)	Day 1: median (IQR): 2 (1.5 to 2.5) Day 5: median (IQR): 2 (1.5 to 2.5)	Day 1: median (IQR): 2 (1.5 to 3) Day 5: median (IQR:) 2 (1 to 2.5)		Day 1: 0.70 Day 5: 0.15	Corley 2014
Atelectasis (chest X‐ray)	Day 1: mean (SD): 4.8 (± 1.9) Day 3: mean (SD): 4.8 (± 1.9)	Day 1: mean (SD) 4.9 (± 1.8) Day 3 mean (SD) 4.7 (± 2.1)		Day 1: 0.63 Day 3: 0.69	Parke 2013a
Long‐term PaCO₂ (at 48 hours; mmHg)	Mean (SD): 41.3 (± 7.5)	Mean (SD): 37.2 (± 9.6)	MD 4.10, 95% CI ‐0.43 to 8.63		Hu 2020
Short‐term respiratory rate (at 6 hours; breaths per minute)	Median (IQR): 25 (20 to 30)	Median (IQR): 26 (21 to 31)		Not reported	Azoulay 2018
Long‐term respiratory rate (at 120 minutes; breaths per minute)	Median (IQR): 25 (22 to 29)	Median (IQR) 25 (21 to 31)		Not reported	Lemiale 2015
Length of hospital stay (days)	Median (IQR): 24 (14 to 40)	Median (IQR): 27 (15 to 42)		0.60	Azoulay 2018
Length of hospital stay (days)	Median (IQR): 12 (7 to 20)	Median (IQR): 11 (7 to 18)		0.58	Futier 2016
Length of hospital stay (days)	Median (IQR): 11(6 to 15)	Median (IQR): 12 (6 to 16)		0.76	Hernandez 2016b
Length of hospital stay (days)	Median (IQR): 7 (6 to 9)	Median (IQR): 9 (7 to 6)		0.012	Zochios 2018
Participant‐reported outcomes Dyspnoea Modified Borg scale (0 = no dyspnoea, 10 = maximal dyspnoea	Median (IQR): 1 (0 to 3)	Median (IQR): 0 (0 to 1)		0.008	Corley 2014
Participant‐reported outcomes Dyspnoea Scale of 0 to 10 (0 = absence of dyspnoea, 10 = worst possible dyspnoea)	Median (IQR): 3 (2 to 6)	Median (IQR): 3 (5 to 9)		0.40	Lemiale 2015
Participant‐reported outcomes Dyspnoea Scale of 0 to 10 (0 = no dyspnoea, 10 = maximal dyspnoea). Authors reported proportion of patients with improvement	Mean (SD): 1.6 (1.2)	Mean (SD): 2.9 (1.5)	MD ‐1.3, 95% CI ‐2.60 to 0.00	0.04	Rittayamai 2014
Participant‐reported outcomes Dry mouth Scale of 0 to 10 (0 = no dryness, 10 = maximum dryness)	Mean (SD) 3.6 (2.5)	Mean (SD) 5 (3.1)	MD ‐1.40, 95% CI ‐2.68 to ‐0.12	0.016	Maggiore 2014
Cost comparison of treatment Total hospitalization expenditure, $	Mean (SD): 11522.65 (762.45)	Mean (SD): 12219.73 (1028.66)		0.001	Yu 2017
^acalculated using RevMan Web 2019 ^bas reported by study authors
CI: confidence interval HFNC: high‐flow nasal cannulae ICU: intensive care unit IQR: interquartile range MD: mean difference PaO₂/FiO₂: ratio of partial pressure of arterial oxygen to fraction of inspired oxygen PaCO₂: partial pressure of carbon dioxide in arterial blood SD: standard deviation

Table 1. Comparison 1 (HFNC vs standard oxygen therapy): continuous outcomes from single studies

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Table 2. Comparison 1 (HFNC vs standard oxygen therapy): dichotomous data from studies not included in meta‐analysis

Additional outcomes	HFNC n/N	Standard oxygen therapy n/N	Effect estimate^a	Study
Atelectasis	2/56	5/54	RR 0.39, 95% CI 0.08 to 1.90	Yu 2017
Adverse events Ventilator‐acquired tracheobronchitis	3/264	7/263	RR 0.43, 95% CI 0.11 to 1.63	Hernandez 2016b
Adverse events Abdominal distension	3/56	0/54	RR 6.75, 95% CI 0.36 to 127.76	Yu 2017
Participant‐reported outcomes Dyspnoea (any improvement; using categorical data reported as marked improvement, slight improvement, no change, slight deterioration, marked deterioration)	65/106	31/94	RR 1.86, 95% CI 1.34 to 2.57	Frat 2015
Participant‐reported outcomes Dry mouth (data included dry mouth, nose, or throat)	18/47	30/43	RR 0.55, 95% CI 0.36 to 0.83	Vourc'h 2020 Vourc'h 2020
Participant‐reported outcomes Throat and nasal pain	1/56	7/54	RR 0.14, 95% CI 0.02 to 1.08	Yu 2017
^acalculated using RevMan Web 2019
CI: confidence interval HFNC: high‐flow nasal cannulae N: total number of participants per group n: number of participants who had an event RR: risk ratio

Table 2. Comparison 1 (HFNC vs standard oxygen therapy): dichotomous data from studies not included in meta‐analysis

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Table 3. Comparison 1 (HFNC vs standard oxygen therapy): summary effects of additional outcomes

Outcome	Study IDs	Effect estimate (short‐term)	Effect estimate (long‐term)	Comment
Duration of respiratory support	Parke 2013a	MD ‐6.00 hours, 95% CI ‐13.77 to 1.77; 1 study, 340 participants; Table 1	‐
Long‐term PaO₂/FiO₂	Maggiore 2014; Vourc'h 2020	‐	MD 27.97, 95% CI 5.60 to 50.33; 2 studies, 195 participants; I² = 81%; Analysis 1.7
Atelectasis	Yu 2017	RR 0.39, 95% CI 0.08 to 1.90; 1 study; 99 participants; Table 2	‐	Additional data available from 2 studies (Corley 2014; Parke 2013a)^a; see Table 1
PaO₂	Frat 2015; Hu 2020; Parke 2011; Maggiore 2014; Song 2017	MD 4.92 mmHg, 95% CI ‐1.24 to 11.07; 4 studies, 415 participants; I² = 47%; Analysis 1.8	MD 12.27 mmHg, 95% CI 7.51 to 17.04; 2 studies, 644 participants; I² = 0%; Analysis 1.8
SpO₂	Maggiore 2014; Parke 2011; Parke 2013a; Rittayamai 2014; Song 2017	MD 0.79 %, 95% CI ‐0.29 to 1.88; 5 studies, 572 participants; I² = 88%; Analysis 1.9	MD 1.28 %, 95% CI 0.02 to 2.55; 2 studies, 445 participants; I² = 81%; Analysis 1.9	Long‐term effect estimate was significant (P = 0.05), however, the high number of comparisons in this review limits our interpretation of this result.
PaCO₂	Frat 2015 Frat 2015; Hernandez 2016b; Hu 2020; Maggiore 2014; Parke 2011; Parke 2013a; Song 2017	MD ‐1.05 mmHg, 95% CI ‐2.24 to ‐0.13; 5 studies, 755 participants; I² = 28%; Analysis 1.10	MD 4.10 mmHg, 95% CI ‐0.43 to 8.63; 1 study, 56 participants; Table 1
Respiratory rate	Corley 2014; Frat 2015; Hu 2020; Maggiore 2014; Parke 2011; Parke 2013a; Rittayamai 2014; Song 2017; Vourc'h 2020	MD ‐2.02 breaths/min, 95% CI ‐3.66 to ‐0.37; 7 studies, 1017 participants; I² = 87%; Analysis 1.11	MD ‐2.01 breaths/min, 95% CI ‐4.39 to 0.37; 4 studies, 591 participants; I² = 92%; Analysis 1.11	Additional data available from 2 studies (Azoulay 2018; Lemiale 2015)^a; see Table 1
Additional adverse events: ventilator‐acquired tracheobronchitis	Hernandez 2016b	RR 0.43, 95% CI 0.11 to 1.63; 1 study, 527 participants; Table 2	‐
Additional adverse events: abdominal distension	Yu 2017	RR 6.75, 95% CI 0.36 to 127.76; 1 study, 110 participants; Table 2	‐
Length of hospital stay	Brainard 2017; Parke 2013a ; Yu 2017	MD ‐0.32 days, 95% CI ‐1.32 to 0.68; 3 studies, 494 participants; I² = 47%; Analysis 1.12	‐	Additional data available from 4 studies (Azoulay 2018; Futier 2016; Hernandez 2016b; Zochios 2018)^ab; see Table 1.
Other participant‐reported outcomes Dyspnoea	Frat 2015; Rittayamai 2014	MD ‐1.30, 95% CI ‐2.60 to 0.00; 1 study, 17 participants; Table 1 RR 1.86, 95% CI 1.34 to 2.57; 1 study, 200 participant; Table 2		Additional data available from 3 studies (Corley 2014; Lemiale 2015; Rittayamai 2014)^a; see Table 1. Azoulay 2018 data reported in figures from which numerical data could not be extracted. Study authors reported no significant difference between groups.
Other participant‐reported outcomes Dry mouth	Maggiore 2014; Vourc'h 2020	RR 0.55, 95% CI 0.36 to 0.83; 1 study, 90 participants; Table 2 MD ‐1.40, 95% CI ‐2.68 to ‐0.12; 1 study, 80 participants; Table 1	‐	Additional data available from Maggiore 2014 reported in Table 1. Additional data from Vourc'h 2020 reported in Table 2. Cuquemelle 2012 effect size was not reported but the authors stated there was no evidence of a difference between groups.
Other participant‐reported outcomes Throat or nasal pain	Yu 2017	RR 0.14, 95% CI 0.02 to 1.08; 1 study, 110 participants; Table 2	‐
Other participant‐reported outcomes Treatment withdrawn due to discomfort	Futier 2016	RR 17.62, 95% CI 1.03 to 301.65; 1 study, 220 participants; Table 2	‐
Other participant‐reported outcomes Refusal to continue treatment	Futier 2016; Parke 2013a	RR 26.89, 95% CI 3.67 to 197.32; 2 studies, 560 participants; Analysis 1.13	‐	Azoulay 2018 reported participant discontinuation in HFNC group due to discomfort, but it was unclear whether any participants in the control group discontinued due to discomfort.
Cost comparison of treatment	Yu 2017	‐	‐	Mean costs reported for HFNC group only. See Table 1
^aWe did not combine data from these studies in analyses because data were reported as median values, or did not include relevant distribution variables for meta‐analysis with other studies ^bFrom visual inspection, we noted that these data were likely to be right skewed due to the comparable magnitudes of the mean and standard deviation. This is expected for outcomes such a length of hospital stay due to most participants being discharged in a short time period with some outliers staying significantly longer. However, right skew introduces artefact into calculation of the effect estimate, limiting the interpretation of the result.
CI: confidence interval FiO2: fraction of inspired oxygen HFNC: high flow nasal cannula(e) MD: mean difference PaCO₂: carbon dioxide clearance PaO₂: partial pressure of arterial oxygen RR: risk ratio SpO₂: oxygen saturation

Table 3. Comparison 1 (HFNC vs standard oxygen therapy): summary effects of additional outcomes

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Table 4. Comparison 1 (HFNC vs standard oxygen therapy): sensitivity analysis

Risk of selection: studies excluded from primary analysis owing to high or unclear risk of selection bias for random sequence generation or allocation concealment
Important outcomes	Excluded studies	Effect of sensitivity analysis
Failure of treatment	Frat 2015; Hu 2020; Lemiale 2015; Maggiore 2014; Song 2017; Yu 2017	Effect estimate no longer indicated improvement with HFNC use (RR 0.85, 95% CI 0.62 to 1.17; 9 studies, 2457 participants; I² = 55%)
In‐hospital mortality	Frat 2015; Hu 2020; Maggiore 2014; Yu 2017	Interpretation of the effect estimate remained the same
Important adverse events: pneumonia	Frat 2015; Yu 2017	Interpretation of the effect estimate remained the same
Important adverse events: nasal mucosa or skin trauma	‐	‐
Length of ICU stay	Brainard 2017; Frat 2015; Maggiore 2014; Yu 2017	Interpretation of the effect estimate remained the same
PaO₂/FiO₂ up to 24 hours	Frat 2015; Maggiore 2014; Parke 2011	Effect estimate indicated higher PaO₂/FiO₂ when standard oxygen therapy was used (MD 25.28 mmHg, 95% CI 7.23 to 43.32; 2 studies, 245 participants; I² = 0%)
Comfort (short‐term)	Frat 2015; Maggiore 2014; Rittayamai 2014	Interpretation of the effect estimate remained the same
Comfort (long‐term)	Maggiore 2014;	Interpretation of the effect estimate remained the same
High risks of other bias: studies excluded from primary analysis owing to high risks of other bias
Outcome	Excluded studies	Effect of sensitivity analysis
Failure of treatment	Fernandez 2017; Hu 2020; Parke 2011; Parke 2013a; Zochios 2018 (selective reporting bias) Frat 2015 (selective reporting bias, and differences in treatment in the HFNC group)	Interpretation of the effect estimate remained the same
In‐hospital mortality	Fernandez 2017; Frat 2015; Hu 2020; Parke 2013a; Zochios 2018 (selective reporting bias) Frat 2015 (differences in treatment in the HFNC group)	Interpretation of the effect estimate remained the same
Important adverse events: pneumonia	Frat 2015 (selective reporting bias, and differences in treatment in the HFNC group)	Interpretation of the effect estimate remained the same
Important adverse events: nasal mucosa or skin trauma	‐	‐
Length of ICU stay	Brainard 2017 (attrition bias) Frat 2015 (selective reporting bias, and differences in treatment in the HFNC group) Parke 2013a (selective reporting bias)	Interpretation of the effect estimate remained the same
PaO₂/FiO₂ up to 24 hours	Frat 2015 (selective reporting bias, and differences in treatment in the HFNC group) Parke 2011 (selective reporting bias)	Effect estimate indicated higher PaO₂/FiO₂ when standard oxygen therapy was used (MD 29.28 mmHg, 95% CI 13.86 to 44.70; 3 studies, 350 participants; I² = 0%)
Comfort (short‐term)	Frat 2015 (selective reporting bias, and differences in treatment in the HFNC group) Parke 2013a (selective reporting bias)	Interpretation of the effect estimate remained the same
Comfort (long‐term)	Parke 2013a (selective reporting bias)	Effect estimate indicated improved comfort when HFNC was used (MD ‐2.10, 95% CI ‐3.16 to ‐1.04; 1 study, 105 participants)
Fixed effect versus random effects: we re‐analysed the data using a fixed‐effect model
Outcomes	Effect of sensitivity analysis
Failure of treatment In‐hospital mortality Important adverse events: pneumonia Important adverse events: nasal mucosa or skin trauma Length of ICU stay PaO₂/FiO₂ up to 24 hours Comfort (short‐term) Comfort (long‐term)	Interpretation of the effect estimate for all outcomes remained the same
Funding: studies excluded from analysis in which funding was from commercial sources
Outcome	Excluded studies	Effect of sensitivity analysis
Failure of treatment	Azoulay 2018; Corley 2014; Frat 2015; Hernandez 2016b; Lemiale 2015; Maggiore 2014; Parke 2011; Parke 2013a; Zochios 2018	Interpretation of the effect estimate remained the same
In‐hospital mortality	Azoulay 2018; Hernandez 2016b; Maggiore 2014; Parke 2013a; Zochios 2018	Interpretation of the effect estimate remained the same
Important adverse events: pneumonia	Frat 2015; Hernandez 2016b	Interpretation of the effect estimate remained the same
Important adverse events: nasal mucosa or skin trauma	Hernandez 2016b	Interpretation of the effect estimate remained the same
Length of ICU stay	Corley 2014; Frat 2015; Maggiore 2014; Parke 2013a	Interpretation of the effect estimate remained the same
PaO₂/FiO₂ up to 24 hours	Corley 2014; Frat 2015; Maggiore 2014; Parke 2013a	Interpretation of the effect estimate remained the same (only one study remaining in analysis)
Comfort (short‐term)	Frat 2015; Maggiore 2014; Parke 2013a	Interpretation of the effect estimate remained the same (only one study remaining in analysis)
Comfort (long‐term)	Maggiore 2014; Parke 2013a	No studies remaining in analysis
CI: confidence interval MD: mean difference RR: risk ratio PaO₂/FiO₂: partial pressure of arterial oxygen/fraction of inspired oxygen

Table 4. Comparison 1 (HFNC vs standard oxygen therapy): sensitivity analysis

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Table 5. Comparison 2 (HFNC vs NIV or NIPPV): dichotomous outcomes from single studies

Important outcomes	HFNC n/N	NIV or NIPPV n/N	Effect estimate^a	Study ID
Participant‐reported outcomes Comfort	74/84	57/84	RR 1.30, 95% CI 1.10 to 1.53	Cong 2019
Adverse events Pneumothorax	8/414	7/416	RR 1.15, 95% CI 0.42 to 3.14	Stephan 2015
Additional outcomes	HFNC n/N	NIV or NIPPV n/N	Effect estimate^a	Study ID
Adverse events Ventilator‐acquired tracheobronchitis	11/290	18/314	RR 0.66, 95% CI 0.32 to 1.38	Hernandez 2016b
^acalculated using RevMan Web 2019
CI: confidence interval HFNC: high‐flow nasal cannulae N: total number of participants in the group n: number of participants who had an event RR: risk ratio

Table 5. Comparison 2 (HFNC vs NIV or NIPPV): dichotomous outcomes from single studies

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Table 6. Comparison 2 (HFNC vs NIV or NIPPV): continuous outcomes for single studies

Important outcomes	HFNC	NIV or NIPPV	Effect estimate^a	P value^b	Study ID
Length of ICU stay (days)	Median (IQR): 9 (4 to 19)	Median (IQR): 10.5 (5 to 19)		Not reported	Hernandez 2016a
Length of ICU stay (days)	Median (IQR) 6 (4 to 10)	Median (IQR) 6 (4 to 10)		0.77	Stephan 2015
Short‐term comfort (1 hour) 5‐point scale of 'poor', 'acceptable', or 'good'	Poor: 16.7% Acceptable: 31.0% Good: 51.0%	Poor: 17.8% Acceptable: 29.3% Good: 53.0%		0.32	Stephan 2015
Long‐term comfort (day 3) 5‐point scale of 'poor', 'acceptable', or 'good'	Poor: 21% Acceptable: 32.4% Good: 47%	Poor: 21% Acceptable: 31% Good: 48.3%		> 0.99	Stephan 2015
Additional outcomes	HFNC	NIV or NIPPV	Effect estimate^a	P value^b	Study ID
Long‐term PaO₂ (mmHg)	Mean (SD): 81.87 (15.27)	Mean (SD): 82.22 (15.64)	MD ‐0.35, 95% CI ‐5.02 to 4.32		Cong 2019
Long‐term SpO₂ (%)	Mean (SD): 87.83 (8.16%)	Mean (SD): 88.65 (7.15)	MD ‐0.82, 95% CI ‐3.14 to 1.50		Cong 2019
Long‐term SpO₂ (%)	Mean (SD): 91.93 (4.35)	Mean (SD): 92.75 (4.07)	MD ‐0.82, 95% CI ‐2.09 to 0.45		Cong 2019
Short‐term PaCO₂ (mmHg) (6 to 12 hours)	Mean (95% CI) 38.2 (37.6 to 38.9)	Mean (95% CI) 39.3 (38.6 to 40.0)		0.19	Stephan 2015
Long‐term PaCO₂ (mmHg)	Mean (SD) 81.87 (15.27)	Mean (SD) 82.22 (15.64)	MD ‐0.35, 95% CI ‐5.02 to 4.32		Cong 2019
Long‐term respiratory rate (breaths/min)	Mean (SD) 22.4 (4.4)	Mean (SD) 21 (4.5)	MD 1.40, 95% CI ‐1.36 to 4.16		Jing 2019
Length of hospital stay (days)	Median (IQR): 23 (14 to 46)	Median (IQR): 26 (16 to 37)		Not reported	Hernandez 2016a
Length of hospital stay (days)	Median (IQR) 13 (9 to 22)	Median (IQR) 14 (9 to 20)		0.59	Stephan 2015
Length of hospital stay (days)	Mean (SD): 18.04 (6.15)	Mean (SD): 18.31	MD ‐0.27 days, 95% CI ‐2.26 to 1.72		Cong 2019
^acalculated using RevMan Web 2019 ^bas reported by study authors
CI: confidence interval ICU: intensive care unit IQR: interquartile range MD: mean difference PaCO₂: partial pressure of carbon dioxide in arterial blood PaO₂/FiO₂: ratio of partial pressure of arterial oxygen to fraction of inspired oxygen

Table 6. Comparison 2 (HFNC vs NIV or NIPPV): continuous outcomes for single studies

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Table 7. Comparison 2 (HFNC vs NIV or NIPPV): summary effects of additional outcomes

Additional outcomes	Study IDs	Effect estimate (short‐term)	Effect estimate (long‐term)	Comment
Duration of respiratory support	Cong 2019; Jing 2019	MD ‐6.12 hours, 95% CI ‐54.61 to 42.37; 2 studies, 210 participants; I² = 60%; Analysis 2.7	‐	We noted a wide variation in results between these studies; this variation may be caused by differences in illness severity in the included participants in each study.
Long‐term PaO₂/FiO₂	Jing 2019; Stephan 2015	‐	MD ‐31.67 mmHg, 95% CI ‐49.37 to ‐13.97; 2 studies, 344 participants; I² = 0%; Analysis 2.8
PaO₂	Cong 2019; Frat 2015	MD ‐9.57 mmHg, 95% CI ‐30.25 to 11.11; 2 studies, 384 participants; I² = 89%; Analysis 2.9	MD ‐0.35 mmHg, 95% CI ‐5.02 to 4.32; 1 study, 168 participants; Table 6
SpO₂	Cong 2019	MD ‐0.82%, 95% CI ‐3.14 to 1.50; 1 study, 168 participants; Table 6	MD ‐0.82%, 95% CI ‐2.09 to 0.45; 1 study, 168 participants; Table 6
PaCO₂	Cong 2019; Frat 2015; Jing 2019; Stephan 2015	MD ‐0.46 mmHg, 95% CI ‐2.08 to 1.16; 4 studies, 1254 participants; I² = 49%; Analysis 2.10	MD ‐1.80 mmHg, 95% CI ‐5.57 to 1.98; 2 studies, 208 participants; I² = 0%; Analysis 2.10
Respiratory rate	Chanques 2013; Frat 2015; Jing 2019; Stephan 2015	MD ‐1.06 breaths/min, 95% CI ‐1.80 to ‐0.32; 4 studies, 1090 participants; I² = 0%; Analysis 2.11	MD 1.40 breaths/min, 95% CI ‐1.36 to 4.16; 1 study, 40 participants; Table 6
Other adverse events Ventilator‐acquired tracheobronchitis	Hernandez 2016a	RR 0.66, 95% CI 0.32 to 1.38; 1 study, 604 participants; Table 5	‐
Length of hospital stay	Cong 2019	MD ‐0.27 days, 95% CI ‐2.26 to 1.72; 1 study, 168 participants; Table 6	‐	Additional data available from 2 studies (Hernandez 2016a; Stephan 2015)^ab; see Table 6
Other participant‐reported outcomes Dyspnoea	Frat 2015; Stephan 2015	RR 1.05, 95% CI 0.74 to 1.48; 2 studies, 1023 participants; I² = 85 %; Analysis 2.12	‐
^aWe did not combine data from these studies in analyses because data were reported as median values ^bFrom visual inspection, we noted that these data were likely to be right skewed due to the comparable magnitudes of the mean and standard deviation. This is expected for outcomes such as length of hospital stay due to most participants being discharged in a short time period with some outliers staying significantly longer. However, right skew introduces artefact into calculation of the effect estimate, limiting the interpretation of the result.
CI: confidence interval MD: mean difference PaCO₂: partial pressure of carbon dioxide in arterial blood PaO₂/FiO₂: ratio of partial pressure of arterial oxygen to fraction of inspired oxygen RR: risk ratio SpO₂: oxygen saturation

Table 7. Comparison 2 (HFNC vs NIV or NIPPV): summary effects of additional outcomes

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Table 8. Comparison 2 (HFNC vs NIV or NIPPV): sensitivity analysis

Risk of selection: studies excluded from primary analysis owing to high or unclear risk of selection bias for random sequence generation or allocation concealment
Important outcomes	Excluded studies	Effect of sensitivity analysis
Failure of treatment	Frat 2015; Shebl 2018; Stephan 2015	Interpretation of the effect estimate remained the same
In‐hospital mortality	Frat 2015; Shebl 2018; Stephan 2015	Interpretation of the effect estimate remained the same
Important adverse events: pneumonia, or barotrauma	NA	NA. Only one study included in primary analyses for these outcomes
Length of ICU stay	Frat 2015	Interpretation of the effect estimate remained the same (only one study remaining in analysis)
PaO₂/FiO₂ up to 24 hours	Frat 2015; Stephan 2015	Effect estimate indicated no evidence of a difference between types of respiratory support used (MD ‐9.30 mmHg, 95% CI ‐80.37 to 61.77; 1 study, 40 participants)
Comfort (short‐term)	Frat 2015	Interpretation of the effect estimate remained the same (only one study remaining in analysis)
Comfort (long‐term)	NA	NA. Only one study included in primary analysis for this outcome
High risks of other bias: studies excluded from primary analysis owing to high risks of other bias
Outcome	Excluded studies	Effect of sensitivity analysis
Failure of treatment	Frat 2015 (selective reporting bias, and differences in treatment in the HFNC group)	Interpretation of the effect estimate remained the same
In‐hospital mortality	Frat 2015 (selective reporting bias, and differences in treatment in the HFNC group)	Interpretation of the effect estimate remained the same
Important adverse events: pneumonia	Frat 2015 (selective reporting bias, and differences in treatment in the HFNC group)	Interpretation of the effect estimate remained the same
Important adverse events: barotrauma	NA	NA. Only one study included in primary analysis for this outcome
Length of ICU stay	Frat 2015 (selective reporting bias, and differences in treatment in the HFNC group)	Interpretation of the effect estimate remained the same (only one study remaining in analysis)
PaO₂/FiO₂ up to 24 hours	Frat 2015 (selective reporting bias, and differences in treatment in the HFNC group)	Interpretation of the effect estimate remained the same
Comfort (short‐term)	Frat 2015 (selective reporting bias, and differences in treatment in the HFNC group)	Interpretation of the effect estimate remained the same (only one study remaining in analysis)
Comfort (long‐term)	NA	NA. Only one study included in primary analysis for this outcome
Fixed effect versus random effects: we re‐analysed the data using a fixed‐effect model
Outcomes	Effect of sensitivity analysis
Failure of treatment In‐hospital mortality Important adverse events: pneumonia or barotrauma Length of ICU stay PaO₂/FiO₂ up to 24 hours Comfort (short‐term) Comfort (long‐term)	Interpretation of the effect estimate for all outcomes remained the same
Funding: studies excluded from analysis in which funding was from commercial sources
Outcome	Excluded studies	Effect of sensitivity analysis
Failure of treatment	Frat 2015	Interpretation of the effect estimate remained the same
In‐hospital mortality	Frat 2015	Interpretation of the effect estimate remained the same
Important adverse events: pneumonia	Frat 2015	Interpretation of the effect estimate remained the same
Important adverse events: barotrauma	Frat 2015	NA. Only one study included in primary analysis for this outcome
Length of ICU stay	Frat 2015	Interpretation of the effect estimate remained the same (only one study remaining in analysis)
PaO₂/FiO₂ up to 24 hours	Frat 2015	Interpretation of the effect estimate remained the same
Comfort (short‐term)	Frat 2015	Interpretation of the effect estimate remained the same (only one study remaining in analysis)
Comfort (long‐term)	Frat 2015	NA. Only one study included in primary analysis for this outcome

CI: confidence interval ICU: intensive care unit MD: mean difference NA: not applicable PaO₂/FiO₂: partial pressure of arterial oxygen/fraction of inspired oxygen

Table 8. Comparison 2 (HFNC vs NIV or NIPPV): sensitivity analysis

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Comparison 1. HFNC versus standard oxygen therapy

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1.1 Treatment failure (escalation of respiratory support to NIV, NIPPV or invasive ventilation) Show forest plot	15	3044	Risk Ratio (M‐H, Random, 95% CI)	0.62 [0.45, 0.86]

1.1.1 Post‐extubation respiratory support	11	1912	Risk Ratio (M‐H, Random, 95% CI)	0.50 [0.30, 0.86]
1.1.2 Respiratory support without prior use of mechanical ventilation	4	1132	Risk Ratio (M‐H, Random, 95% CI)	0.85 [0.68, 1.08]
1.2 In‐hospital mortality Show forest plot	11	2673	Risk Ratio (M‐H, Random, 95% CI)	0.96 [0.82, 1.11]

1.3 Important adverse events Show forest plot	5		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

1.3.1 Pneumonia	4	1057	Risk Ratio (M‐H, Random, 95% CI)	0.72 [0.48, 1.09]
1.3.2 Nasal mucosa or skin trauma	2	617	Risk Ratio (M‐H, Random, 95% CI)	3.66 [0.43, 31.48]
1.4 Length of ICU stay (days) Show forest plot	6	970	Mean Difference (IV, Random, 95% CI)	0.13 [‐0.02, 0.28]

1.5 Short‐term respiratory effects: PaO ₂/FiO ₂ (mmHg) Show forest plot	5	600	Mean Difference (IV, Random, 95% CI)	10.34 [‐17.31, 38.00]

1.6 Comfort Show forest plot	4		Mean Difference (IV, Random, 95% CI)	Subtotals only

1.6.1 Short‐term effect	4	662	Mean Difference (IV, Random, 95% CI)	0.31 [‐0.60, 1.22]
1.6.2 Long‐term effect	2	445	Mean Difference (IV, Random, 95% CI)	0.59 [‐2.29, 3.47]
1.7 Long‐term respiratory effects: PaO ₂/FiO ₂ (mmHg) Show forest plot	2	195	Mean Difference (IV, Random, 95% CI)	34.28 [‐19.25, 87.80]

1.8 Short‐term and long‐term respiratory effects: PaO ₂ (mmHg) Show forest plot	5		Mean Difference (IV, Random, 95% CI)	Subtotals only

1.8.1 Short‐term effects	4	415	Mean Difference (IV, Random, 95% CI)	4.92 [‐1.24, 11.07]
1.8.2 Long‐term effects	2	644	Mean Difference (IV, Random, 95% CI)	12.27 [7.51, 17.04]
1.9 Short‐term and long‐term respiratory effects: SpO ₂ (%) Show forest plot	5		Mean Difference (IV, Random, 95% CI)	Subtotals only

1.9.1 Short‐term effects	5	572	Mean Difference (IV, Random, 95% CI)	0.79 [‐0.29, 1.88]
1.9.2 Long‐term effects	2	445	Mean Difference (IV, Random, 95% CI)	1.28 [0.02, 2.55]
1.10 Short‐term respiratory effects: PaCO ₂ (mmHg) Show forest plot	5	755	Mean Difference (IV, Random, 95% CI)	‐1.05 [‐2.24, 0.13]

1.11 Short‐term and long‐term respiratory rate (breaths/min) Show forest plot	9	1608	Mean Difference (IV, Random, 95% CI)	‐2.01 [‐3.19, ‐0.83]

1.11.1 Short‐term effects	8	1017	Mean Difference (IV, Random, 95% CI)	‐2.02 [‐3.66, ‐0.37]
1.11.2 Long‐term effects	4	591	Mean Difference (IV, Random, 95% CI)	‐2.01 [‐4.39, 0.37]
1.12 Length of hospital stay (days) Show forest plot	2	450	Mean Difference (IV, Random, 95% CI)	‐0.11 [‐0.43, 0.20]

1.13 Refusal to continue with treatment Show forest plot	2	560	Risk Ratio (M‐H, Random, 95% CI)	26.89 [3.67, 197.32]

Comparison 1. HFNC versus standard oxygen therapy

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Comparison 2. HFNC versus NIPPV or NIV

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
2.1 Treatment failure (escalation of respiratory support to NIV, NIPPV or invasive ventilation) Show forest plot	5	1758	Risk Ratio (M‐H, Random, 95% CI)	0.98 [0.78, 1.22]

2.1.1 Post‐extubation respiratory support	3	1472	Risk Ratio (M‐H, Random, 95% CI)	1.12 [0.89, 1.41]
2.1.2 Respiratory support without prior use of mechanical ventilation	2	286	Risk Ratio (M‐H, Random, 95% CI)	0.77 [0.58, 1.03]
2.2 In‐hospital mortality Show forest plot	5	1758	Risk Ratio (M‐H, Random, 95% CI)	0.92 [0.64, 1.31]

2.3 Important adverse events: pneumonia Show forest plot	3	1750	Risk Ratio (M‐H, Random, 95% CI)	0.51 [0.17, 1.52]

2.4 Short‐term respiratory effects: PaO ₂/FiO ₂ (mmHg) Show forest plot	3	1086	Mean Difference (IV, Random, 95% CI)	‐58.10 [‐71.68, ‐44.51]

2.5 Length of ICU stay (days) Show forest plot	2	246	Mean Difference (IV, Random, 95% CI)	‐0.72 [‐2.85, 1.42]

2.6 Short‐term comfort (continuous data) Show forest plot	2	258	Mean Difference (IV, Random, 95% CI)	1.33 [0.74, 1.92]

2.7 Duration of respiratory support (hours) Show forest plot	2	210	Mean Difference (IV, Random, 95% CI)	‐6.12 [‐54.61, 42.37]

2.8 Long‐term respiratory effects: PaO ₂/FiO ₂ (mmHg) Show forest plot	2	344	Mean Difference (IV, Random, 95% CI)	‐31.67 [‐49.37, ‐13.97]

2.9 Short‐term respiratory effects: PaO ₂ (mmHg) Show forest plot	2	384	Mean Difference (IV, Random, 95% CI)	‐9.57 [‐30.25, 11.11]

2.10 Short‐term and long‐term respiratory effects: PaCO ₂ (mmHg) Show forest plot	4		Mean Difference (IV, Random, 95% CI)	Subtotals only

2.10.1 Short‐term effects	4	1254	Mean Difference (IV, Random, 95% CI)	‐0.46 [‐2.08, 1.16]
2.10.2 Long‐term effects	2	208	Mean Difference (IV, Random, 95% CI)	‐1.80 [‐5.57, 1.98]
2.11 Short‐term respiratory effects: breaths/min Show forest plot	4	1090	Mean Difference (IV, Random, 95% CI)	‐1.06 [‐1.80, ‐0.32]

2.12 Dyspnoea (any improvement) Show forest plot	2	1023	Risk Ratio (M‐H, Random, 95% CI)	1.05 [0.74, 1.48]

Comparison 2. HFNC versus NIPPV or NIV

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