High flow nasal cannula for respiratory support in term infants

  • Protocol
  • Intervention

Authors

  • Sara Mayfield,

    Corresponding author
    1. Mater Children’s Hospital, Paediatric Critical Care Research Group, South Brisbane, Queensland, Australia
    2. School of Nursing and Midwifery, The University of Queensland, Herston, Australia
    3. Mater Research Institute, South Brisbane, Australia
    • Sara Mayfield, Paediatric Critical Care Research Group, Mater Children’s Hospital, South Brisbane, Queensland, 4101, Australia. Sara.mayfield@mater.org.au.

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  • Jacqueline Jauncey-Cooke,

    1. Mater Children’s Hospital, Paediatric Critical Care Research Group, South Brisbane, Queensland, Australia
    2. School of Nursing and Midwifery, The University of Queensland, Herston, Australia
    3. Mater Research Institute, South Brisbane, Australia
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  • Andreas Schibler,

    1. Mater Children’s Hospital, Paediatric Critical Care Research Group, South Brisbane, Queensland, Australia
    2. Mater Research Institute, South Brisbane, Australia
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  • Judith L Hough,

    1. Mater Children’s Hospital, Paediatric Critical Care Research Group, South Brisbane, Queensland, Australia
    2. Mater Research Institute, South Brisbane, Australia
    3. Australian Catholic University, School of Physiotherapy, Banyo, Australia
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  • Fiona Bogossian

    1. School of Nursing and Midwifery, The University of Queensland, Herston, Australia
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Abstract

This is the protocol for a review and there is no abstract. The objectives are as follows:

To assess the safety and efficacy of high flow nasal cannula oxygen therapy for respiratory support in term infants. We will compare HFNC with other forms of non-invasive support including:

  • low flow nasal cannula oxygen

  • head box oxygen

  • nasal continuous positive airway pressure

  • non-invasive positive pressure ventilation

  • alternative forms of HFNC (such as non humidified or humidified)

Subgroup analysis will be undertaken to determine efficacy of HFNC in term infants with different underlying conditions. These conditions include congestive heart failure, pneumonia/pneumonitis (aspiration, bacterial, or viral)

Background

Description of the condition

Respiratory failure or respiratory distress in infants is the most common reason for non-elective admission to hospitals and intensive care units. Support of breathing and ventilation is central to the care of these critically ill patients. Support may be needed in term infants due to respiratory infections (bronchiolitis) or pneumonia, congestive heart failure, parenchymal lung disease, trauma or post-surgical interventions. Respiratory support can be delivered invasively via endotracheal tubes and mechanical ventilation or non-invasively in the form of continuous positive airway pressure or oxygen therapy. Infants with significant hypoxaemia or respiratory insufficiency often require invasive support, which may lead to various complications such as ventilator-induced lung injury and ventilator-associated pneumonia (ARDS Network 2000; Dahlem 2003).

Non-invasive methods of respiratory support may avoid some of the additional harm associated with the use of endotracheal tubes and mechanical ventilation. Non-invasive devices that deliver continuous positive airway pressure can reduce an infant's work of breathing, improve functional residual capacity, and avoid the need for invasive forms of support (Frey 2001). This in turn can prevent ventilator-induced lung injury and other complications associated with invasive ventilation (Reid 1984; Thorsteinsson 2002).

However, there are disadvantages with non-invasive methods. They are often cumbersome and the face/nasal/mask interface is often poorly tolerated by infants (Yong 2005 ). This can make the delivery of continuous positive airway pressure variable and result in ineffective ventilation. Providing a system that can deliver continuous positive airway pressure to assist an infant's work of breathing and yet be tolerable is an important consideration in effective non-invasive respiratory support for this age group.

Description of the intervention

Heated, humidified, high flow nasal cannula (HFNC) therapy has recently been introduced to patients across all ages from preterm infants to adults. It is a simple and effective method of providing respiratory support (Campbell 2006; McKiernan 2010; Shoemaker 2007). It allows for high inspired gas flows to be delivered via an air/oxygen blender. The heating and humidification of the gas mixture provides advantages over simple oxygen delivery in that it reduces upper airway mucosal damage, can prevent inflammatory reactions and reduce naso-pulmonary bronchoconstrictor reflexes (Dysart 2009). The inspired oxygen concentration can also be manipulated from 21% to 100% (de Klerk 2008). High flow nasal cannula therapy can be used as an initial form of respiratory support or as a 'step-down' modality after continuous positive airway pressure or intubation/mechanical ventilation. Retrospective studies have shown that the use of HFNC therapy reduced overall ventilator days in term infants and that intubation rates were also greatly reduced (McKiernan 2010; Schibler 2011; Wing 2012). High flow nasal cannula therapy has also been reported to be better tolerated than other forms of non-invasive ventilation, and easier to care for and apply (Roca 2010; Saslow 2006; Spentzas 2009). Furthermore, it may reduce the need for sedation that is often required to help tolerate more uncomfortable forms of respiratory support. However there remains no universally accepted definition as to what constitutes 'high flow'.

How the intervention might work

High flow nasal cannula therapy has been used in preterm and term infants at rates of 1 to 10 L/min (McKiernan 2010; Schibler 2011; Wilkinson 2011). It is suggested that at these rates continuous positive airway pressure is generated.

Other alternative mechanisms of action of HFNC include that the high flows flush the anatomical dead space of the nasopharyngeal cavity resulting in improved alveolar ventilation. It may also wash out carbon dioxide and reduce apnoea caused from hypercapnia, thereby improving overall ventilation (Dysart 2009; Spence 2007). The amount of continuous positive airway pressure generated depends on the flow delivered relative to the size of the infant, size of the nasal cannula and the leak around the nares (Lampland 2009; Screenan 2001). Flow rates (3 to 5 L/min) measured in preterm and term infants revealed that continuous positive airway pressure (measured intra-pharyngeal) generated pressures of 1.7 to 4.8 cm H2O (Spence 2007).

Why it is important to do this review

Intubation and subsequent mechanical ventilation in term infants is known to have many associated risks, such as ventilator-induced lung injury.  Any therapy that may reduce the need for a term infant to be intubated needs to be considered and evaluated. High flow nasal oxygen therapy in infants and children has demonstrated a reduction in intubation rates (McKiernan 2010; Schibler 2011; Wing 2012), and the potential exists for this to be true in term infants.

There is a published Cochrane systematic review on high flow nasal oxygen delivery for preterm respiratory support (Wilkinson 2011). This review concluded that there is insufficient evidence to determine HFNC effectiveness in the preterm population and that more research was needed. At present there are protocols for systematic reviews assessing HFNC effectiveness in the adult population (Corley 2012), in infants with bronchiolitis (Beggs 2014), and in children (Mayfield 2012). However, there is not as yet a review that covers the infant population aged ≥ 37 weeks gestational age with respiratory distress.

High flow nasal cannula therapy has the potential to improve outcomes for critically ill term infants. It is simple to apply and is not resource intensive. While it may reduce intubation rates, it may also be viewed as a step-down therapy between extubation and low flow nasal cannula oxygen delivery. As with all interventions there are concerns over potential complications and adverse events (Hedge 2013). It is important that these are assessed in a systematic review and reported.

Objectives

To assess the safety and efficacy of high flow nasal cannula oxygen therapy for respiratory support in term infants. We will compare HFNC with other forms of non-invasive support including:

  • low flow nasal cannula oxygen

  • head box oxygen

  • nasal continuous positive airway pressure

  • non-invasive positive pressure ventilation

  • alternative forms of HFNC (such as non humidified or humidified)

Subgroup analysis will be undertaken to determine efficacy of HFNC in term infants with different underlying conditions. These conditions include congestive heart failure, pneumonia/pneumonitis (aspiration, bacterial, or viral)

Methods

Criteria for considering studies for this review

Types of studies

We will include prospective randomised controlled trials (RCTs) and quasi randomised controlled trials in term infant populations that investigate the use of high flow nasal cannula oxygen therapy in infants ≥ 37 weeks gestational age to one month postnatal of age. 

Types of participants

We will define term infants as being those aged ≥ 37 weeks gestational age to one month postnatal age. We will exclude preterm infants below 37 gestational weeks. There will be no exclusion based on diagnosis of disease or condition. We will consider two populations of term infants without limits on the period of HFNC:

  1. those infants requiring HFNC as an initial mode of respiratory support, regardless of length of therapy and without a prior period of intermittent positive pressure ventilation ;

  2. those infants requiring HFNC as respiratory support following a period of intermittent positive pressure ventilation i.e. post extubation.

Types of interventions

For the purpose of this review, HFNC oxygen therapy will be defined as flow rates of greater than 2 L/min with a blended air/oxygen system delivered via nasal cannula. Alternative interventions will include: 

  • low flow nasal cannula oxygen (flow rates less than or equal to 2 L/min);

  • head box oxygen;

  • nasal continuous positive airway pressure;

  • non-invasive positive pressure ventilation;

  • HFNC using an alternative technique (e.g. humidified versus non-humidified).

Types of outcome measures

Primary outcomes
  • Death

  • Chronic lung disease (the need for supplemental oxygen as 28 days of life)

  • Treatment failure as indicated by the need for intubation or reintubation (within 24 hours of initial extubation)

Secondary outcomes
  • Duration in hours/days of any form of respiratory support (mechanical ventilation, non invasive ventilation, high flow nasal cannula or oxygen)

  • Length of stay at intensive care unit (ICU) (days)

  • Hospital length of stay (days)

  • Adverse effects

    • Nasal trauma

    • Air leak syndrome

    • Abdominal overdistention

    • Nosocomial pneumonia

Search methods for identification of studies

We will use the standard methods of the Cochrane Neonatal Review Group.

Electronic searches

We will search the current issue of the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library); MEDLINE via Ovid SP (January 1966 to date); EMBASE via Ovid SP (January 1980 to date); CINAHL via EBSCO Host (1982 to date): LILACS via BIREME interface (1982 to date) and Web of Science (1985 to date).

We will search electronic databases of higher degree theses for relevant unpublished trials: Index to Theses (1950 to date), Australian Digital Theses Program (1997 to date) and Proquest Digital Disertations (1980 to date).

We will combine our MEDLINE search strategy with the Cochrane highly sensitive search strategy for identifying RCTs as suggested in the Cochrane handbook for Systematic Reviews of Interventions (Higgins 2011). We will search for clinical trials (publiation type "clinical trial" or "randomised controlled trial") using the MeSH headings: infant, newborn AND oxygen inhalation therapy OR positive pressure ventilation AND the text word "nasal cannula*" OR "nasal prong" OR "nasal cannula". A second search will use the MeSH heading "infant, newborn" in combination with the textword "high flow nasal"(**).

We will not apply any date, language or publications restrictions to our searches.

Searching other resources

We will search the metaRegister of Controlled Trials (http://www.controlled-trials.com/mrct/) and ClinicalTrials.gov (http://clinicaltrials.gov/) for ongoing trials.

We will check conference abstracts for unpublished studies. We will check reference lists of all relevant articles to identify other relevant studies. We will contact authors known in the field to determine if unpublished work is available.

Data collection and analysis

We used the standard search methods of the Cochrane Neonatal Review Group.

Selection of studies

Five review authors (SM, JJC, AS, FB, JH) will undertake the study selection process. Two authors (SM, JH) will independently identify the studies and assess whether they meet the inclusion criteria. We will resolve disagreements by consulting a third author (FB). We will tabulate excluded studies and will document the reason for exclusion. We will compile a list of eligible trials, based on the abstract.

Data extraction and management

Two review authors (SM, JH) will independently perform data extraction using a standardised data extraction form. We will resolve any discrepancies in the data extracted by discussion.

Assessment of risk of bias in included studies

Two authors (SM, JH) will evaluate each included study according to the following headings and associated questions .

  • Selection bias: adequate random sequence generation and allocation concealment?

    • For each included study we will categorise the risk of selection bias as: low risk - adequate (any random process such as random number table, computer random number generator); high risk - inadequate (any non random process such as odd or even date of birth, hospital number); unclear - no or unclear information.

    • For each included study we will categorise the risk of bias regarding allocation concealment as: low risk - adequate (such as telephone or central randomisation or consecutively numbered sealed opaque envelopes); high risk - inadequate (open random allocation, unsealed or non-opaque envelopes, date of birth); unclear risk - no or unclear information provided.

  • Performance bias: blinding?

    • For each included study we will categorise the methods used to blind study personnel from knowledge of which intervention a participant received (as our study population will consist of neonates they would all be blinded to the study intervention) as: low risk - adequate for personnel; high risk - inadequate; unclear - no or unclear information provided.

  • Detection bias:

    • for each study we will categorise the methods used to blind outcome assessors from knowledge of which intervention a participant received. Blinding will be assessed separately for different outcomes or classes of outcomes. We will categorise the methods used with regards to detection bias as: low risk - adequate ( follow up was preformed with assessors blinded to group); high risk - inadequate ( assessors at follow up were aware of group assignment); unclear risk - no or unclear information provided.

  • Detection bias:

    • for each study we will categorise the methods used to blind outcome assessors from knowledge of which intervention a participant received. Blinding will be assessed separately for different outcomes or classes of outcomes. We will categorise the methods used with regards to detection bias as: low risk - adequate ( follow up was preformed with assessors blinded to group); high risk - inadequate ( assessors at follow up were aware of group assignment); unclear risk - no or unclear information provided.

  • Attrition bias:

    • incomplete data addressed?

      • For each included study and for each outcome we will describe the completeness of data including attrition and exclusions from the analysis. We will note whether attrition and exclusions were reported, the numbers included in the analysis at each stage (compared with the total randomised participants), reasons for attrition or exclusion where reported and whether missing data were balances across groups or were related to outcomes. Where sufficient information is reported or supplied by the trial authors we will re-include missing data in the analyses. We will categorise the methods with respect to the risk attrition bias as: low risk - adequate (<10% missing data); high risk - inadequate (>10% missing data); unclear - no or unclear information provided.

  • Reporting bias: free of selective reporting?

    • For each included study we will describe how we investigated the risk of selective outcome reporting bias and what we found. We will assess the methods as: low risk - adequate (where it is clear that all the study's pre-specified outcomes and all expected outcomes of interest to the review have been reported); high risk - inadequate (where not all the study's pre-specified outcomes have bee reported, or one or more reported primary outcomes were not pre-specified, or outcomes of interest are reported incompletely and so cannot be used, or the study fail to include results of a key outcome that would have been expected to have been reported); unclear risk - no or unclear information provided (the study protocol was not available).

  • Other bias; free of other bias?

    • For each included study we will describe any important concerns we have about other possible sources of bias (e.g. whether there was a potential source of bias related to the specific study design or whether the trial was stopped early due to some data-dependent process). We will assess whether each study was free of other problems that could put it at risk of bias as: low risk - no concerns of other bias raised; high risk - concerns raised about multiple looks at the data with the results made known to the investigators, difference in number of patients enrolled in abstract and final publications of the paper; unclear - concerns raised about potential sources of bias that could not be verified by contacting the authors.

  • Overall risk of bias

We will make explicit judgments about whether studies are at high risk of bias, according to the criteria given in the Cochrane handbook for Systematic Reviews of Interventions (Higgins 2011). We will assess the likely magnitude and direction of the bias and whether we consider it is likely to impact on the findings. We will explore the impact of the level of bias through undertaking sensitivity analyses (Sensitivity analysis).

One author (SM) will enter the data into the Cochrane Collaboration's statistical software, Review Manager 2013, with verification of data entry conducted independently by a second author (JJC).

Measures of treatment effect

We will collect the mean and standard deviation for continuous data (such as duration of respiratory support) and analyse it using weighted mean differences (WMDs). We will extract categorical data (such as death or treatment failure) for each intervention group and calculate relative risks (RRs) and risk difference (RDs). For statistically significant RDs, we will calculate the numbers needed to treat (NNTs) and numbers needed to harm (NNHs). For each measure of effect we will calculate the 95% confidence intervals (CIs).

Dealing with missing data

We will contact corresponding authors of the trial reports directly if there is insufficient information or missing data. If there is no response or it is not possible to find them, then we will include the trial in question in the review but we will analyse the effects of its inclusion or exclusion on the overall results as part of the sensitivity analysis.

Assessment of heterogeneity

We will analyse heterogeneity using the Chi2 test on the N-1 degrees of freedom, with an alpha of 0.1 used for statistical significance and with the I2 statistic (Higgins 2011). The values of heterogeneity will be set at:

  • <25%: no heterogeneity;

  • 25-49%: low heterogeneity;

  • 50-74%: moderate heterogeneity;

  • ≥75%: high heterogeneity.

In the presence of heterogeneity, we will conduct a sensitivity analysis to explain the source of heterogeneity. We will use a fixed-effect model if insignificant heterogeneity between trials is found (Higgins 2011).

Assessment of reporting biases

We will calculate funnel plot symmetry to detect any publication bias if there are at least 10 trials included in a meta-analysis..

Data synthesis

We will review the summary tables of included trials to identify clinical heterogeneity amongst trials. We will use Review Manager 2013 to perform a meta-analysis with fixed-effect model for two or more RCTs with comparable populations and treatment interventions and present all our results with 95% CIs.

If different scales are used to measure the same continuous data across trials we will calculate standardised mean differences (SMDs) to determine treatment effect. We will assess WMDs, RRs, RDs, NNTs and/or NNHs. The outcomes of comparable trials will be analysed with 95% CIs to estimate treatment effect. We will compare results using forest plots, with the RR as the point estimate for dichotomous outcomes and WMD as the point estimate for continuous outcomes.

Subgroup analysis and investigation of heterogeneity

We will perform subgroup analysis to explore possible sources of heterogeneity. Heterogeneity could be related to underlying pathophysiological conditions, and flow delivered in relation to weight. We will use a narrative summary of findings where there is clear evidence of heterogeneity amongst trials or calculate RRs with 95% CIs where possible (Sutton 2008).

Appropriate subgroup analyses to undertake include:

  • pneumonia/pneumonitis (aspiration, bacterial or viral);

  • congestive heart failure.

Sensitivity analysis

With an adequate number of studies we will perform a sensitivity analysis for methodological quality and robustness of results using the risk of bias domains.

Acknowledgements

We would like to acknowledge the assistance of the Cochrane Neonatal Review Group in reviewing this protocol.

Contributions of authors

Conceiving the review: Sara Mayfield (SM)

Co-ordinating the review: SM

Undertaking manual searches: SM

Screening search results: SM and Jacqui Jauncey-Cooke (JJC)

Organizing retrieval of papers: SM

Screening retrieved papers against inclusion criteria: SM and JJC

Appraising quality of papers: SM, JJC and Judith Hough (JH)

Abstracting data from papers: SM and JJC

Writing to authors of papers for additional information: SM

Providing additional data about papers: SM

Obtaining and screening data on unpublished studies: SM

Data management for the review: SM, JJC and Fiona Bogossian (FB)

Entering data into Review Manager (RevMan 5.1): SM

RevMan statistical data: SM, JH, FB

Other statistical analysis not using RevMan: JH

Interpretation of data: SM, JJC, FB, JH and Andreas Schibler (AS)

Statistical inferences: SM, JJC, FB, AS

Writing the review: SM

Securing funding for the review: n/a

Performing previous work that was the foundation of the present study:

Guarantor for the review (one author): FB

Person responsible for reading and checking review before submission: JJC, FB, AS and JH

Declarations of interest

Sara Mayfield and Andreas Schibler are working on studies with HFNC in the paediatric intensive care unit where they work. To date the trials are observational in nature and not in line with RCTs, however this may change in the future. However, any trial that may be included from these authors will be acknowledged and assessed by an independent person (JH, FB or JJC).

Andreas Schibler: Fisher and Paykel have supported my research by funding one project and supplying equipment in another.  Neither projects are published as yet, but may be eligible for inclusion in this review.  If any of the studies in the review are deemed to hold a conflict of interest with me, then they will be assessed by an independent person (JH, FB, SM or JJC).

Jacqueline Jauncey-Cooke: none known.

Judith L Hough: none known:

Fiona Bogossian: none known.

Sources of support

Internal sources

  • No sources of support supplied

External sources

  • Eunice Kennedy Shriver National Institute of Child Health and Human Development National Institutes of Health, Department of Health and Human Services, USA.

    Editorial support of the Cochrane Neonatal Review Group has been funded with Federal funds from the Eunice Kennedy Shriver National Institute of Child Health and Human Development National Institutes of Health, Department of Health and Human Services, USA, under Contract No. HHSN275201100016C.

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