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Contemporary Reviews in Critical Care Medicine |

CPAP and High-Flow Nasal Cannula Oxygen in BronchiolitisNoninvasive Respiratory Support in Bronchiolitis FREE TO VIEW

Ian P. Sinha, PhD; Antonia K. S. McBride, MBChB; Rachel Smith, MBChB; Ricardo M. Fernandes, MD
Author and Funding Information

From the Respiratory Unit (Drs Sinha, McBride, and Smith), Alder Hey Children’s Hospital, Liverpool, England; Department of Pediatrics (Dr Fernandes), Santa Maria Hospital, Lisbon Academic Medical Centre, Lisbon, Portugal; and Clinical Pharmacology Unit (Dr Fernandes), Instituto de Medicina Molecular, University of Lisbon, Lisbon, Portugal.

CORRESPONDENCE TO: Ian P. Sinha, PhD, Respiratory Unit, Alder Hey Children’s Hospital, Alder Rd, Liverpool, L12 2AP, England; e-mail: iansinha@liv.ac.uk


Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2015;148(3):810-823. doi:10.1378/chest.14-1589
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Severe respiratory failure develops in some infants with bronchiolitis because of a complex pathophysiologic process involving increased airways resistance, alveolar atelectasis, muscle fatigue, and hypoxemia due to mismatch between ventilation and perfusion. Nasal CPAP and high-flow nasal cannula (HFNC) oxygen may improve the work of breathing and oxygenation. Although the mechanisms behind these noninvasive modalities of respiratory support are not well understood, they may help infants by way of distending pressure and delivery of high concentrations of warmed and humidified oxygen. Observational studies of varying quality have suggested that CPAP and HFNC may confer direct physiologic benefits to infants with bronchiolitis and that their use has reduced the need for intubation. No trials to our knowledge, however, have compared CPAP with HFNC in bronchiolitis. Two randomized trials compared CPAP with oxygen delivered by low-flow nasal cannula or face mask and found some improvements in blood gas results and some physiologic parameters, but these trials were unable to demonstrate a reduction in the need for intubation. Two trials evaluated HFNC in bronchiolitis (one comparing it with headbox oxygen, the other with nebulized hypertonic saline), with the results not seeming to suggest important clinical or physiologic benefits. In this article, we review the pathophysiology of respiratory failure in bronchiolitis, discuss these trials in detail, and consider how future research studies may be designed to best evaluate CPAP and HFNC in bronchiolitis.

Figures in this Article

Bronchiolitis causes significant infant morbidity and mortality in developed1 and developing2 countries. Most bronchiolitis is caused by respiratory syncytial virus (RSV), and almost all infants will have encountered this agent by the age 3 years.3 Other viruses, particularly rhinovirus, human metapneumovirus, and adenovirus, may also be involved as single or dual infections, and the infectious etiology may affect short- and long-term outcomes.4,5 Reported hospital admission rates for bronchiolitis vary from 2% to 10%,2,6 and around 5% to 9% of these will result in admission to critical care because of either respiratory failure or apneas.7,8

The pathogenesis of respiratory failure in bronchiolitis is multifactorial but is mainly a disease of small airway obstruction (Fig 1). RSV infects epithelia, leading to cell death and a complex inflammatory cascade.9,10 Cell debris, ciliary dysfunction, and cytokine release cause intraluminal mucus11 (the plugging of which leads to atelectasis and ventilation-perfusion mismatch), airway wall edema, and interstitial changes leading to decreased lung compliance. A predominantly alveolar presentation causing ARDS has also been described.12

Figure Jump LinkFigure 1 –  Mechanisms of respiratory failure in bronchiolitis and possible actions of CPAP and HFNC. Intraluminal mucus and debris cause airway obstruction (A) and increased resistance (B). Warmed, humidified oxygen can reduce intraluminal mucus (A1), and positive end-expiratory pressure (PEEP) from CPAP (and possibly HFNC) might help to overcome resistance (B1). Intraluminal obstruction causes atelectasis (C). Increased PEEP prevents atelectasis (C1). Increased interstitial edema limits oxygen transport to blood, contributing to hypoxemic respiratory failure (D). CPAP and HFNC are efficient methods of delivering high oxygen concentrations to the lower airways (D1), which may overcome this. All these mechanisms cause respiratory muscle fatigue (E). Overcoming airway resistance (A1 and B1), reducing atelectasis (C1), and increasing oxygen delivery to the blood (D1) can help to reduce this respiratory muscle fatigue (E1). Although primarily a small airways disease, increased respiratory efforts can cause upper airway collapse in infants (F), and PEEP may help to reduce this (F1). HFNC = high-flow nasal cannula.Grahic Jump Location

Infants are especially susceptible to respiratory failure in bronchiolitis because of certain developmental and anatomic factors. Because they breathe largely through the nose, the viral nasal secretions make breathing particularly difficult.13 Their prominent occipital bones cause a tendency to neck flexion and upper airway obstruction.14 Alveoli are still developing in number and function14 as are respiratory muscle fibers, a relatively low proportion of which are fatigue resistant.15 Younger and premature infants may also be vulnerable to RSV (and other virus)-induced central autonomic dysfunction, which could explain their higher risk of apneas.16 Various factors are associated with severe illness, such as age < 3 months,17 ex-prematurity18 (particularly in those with bronchopulmonary dysplasia19), coexisting cardiac disease,20 neuromuscular disease,21 immunodeficiency,21 and other chronic respiratory illness.21

Although large randomized controlled trials (RCTs) have tried to identify interventions that may prevent respiratory failure in bronchiolitis, the mainstays of treatment continue to be adequate respiratory and nutritional support.22 Although nebulized epinephrine and hypertonic saline have emerged as potential options,23-25 evidence to date has been nonconclusive26 and lacking in infants with severe disease or risk factors predicting the need for mechanical ventilation.27

Most infants do not require active respiratory support, and for the majority of those who do, supplementary oxygen therapy will suffice. This has traditionally been delivered by ambient headbox (which can deliver up to around 60% humidified oxygen) or low-flow nasal cannula, which can deliver unwarmed, unhumidified oxygen up to around 2 L/min. The concentration of oxygen delivered is variable and neither measurable nor controllable, and although assumed to be up to 30%, it may in fact be higher in infants.28 In infants with severe respiratory compromise, headbox oxygen and low-flow cannulae treat hypoxemia but do not in themselves overcome airways resistance, reduce the work of breathing and respiratory fatigue, or loosen thick intraluminal mucus. Nasal CPAP and high-flow nasal cannula (HFNC) oxygen theoretically offer at least some of these advantages and are increasingly used as modalities of noninvasive respiratory support for infants with bronchiolitis and respiratory distress. We summarize in this article the physiologic rationale and evidence from clinical research studies for CPAP and HFNC in infants with bronchiolitis. These studies were identified in April 2014 by searching MEDLINE and the Cochrane Central Register of Controlled Trials using terms related to bronchiolitis, RSV, CPAP, and HFNC.

When we consider the pathophysiology of respiratory failure in bronchiolitis, CPAP appears to be an attractive intervention for improving breathing efficiency. In theory, positive end-expiratory pressure (PEEP) increases functional residual capacity by increasing lumen diameter in small airways and, thus, preventing end-expiratory alveolar atelectasis. The increased airway diameter reduces resistance, and the prevention of alveolar atelectasis improves compliance.29

Observational studies describing the physiologic effects of CPAP on infants with bronchiolitis are summarized in Table 1. In four retrospective case series of infants with severe bronchiolitis and impending failure,30,31,38,39 authors described clinical and blood gas parameters within hours of initiating CPAP in intensive care settings. In one study of 23 infants (17 receiving CPAP through nasal cannulae and six through endotracheal tube), three of the 17 babies receiving nasal CPAP subsequently required invasive ventilation.30 In a study of seven infants receiving CPAP through a nasopharyngeal airway, one infant required subsequent invasive ventilation.31 In a another study of 121 infants with severe bronchiolitis, 13 of 53 (26%) receiving nasal CPAP subsequently required invasive ventilation,38 and in a study of nasal CPAP in 65 infants, six (9.2%) required ventilation.39

Table Graphic Jump Location
TABLE 1 ]  Observational Studies Describing the Use of CPAP and HFNC in Bronchiolitis

EDIN = Échelle Douleur Inconfort Nouveau-Né (neonatal pain and discomfort scale); ETT = endotracheal tube; HDU = high-dependency unit; HFNC = high-flow nasal cannula; HR = heart rate; LOS = length of stay; m-WCAS = Modified Wood Clinical Asthma Score; NIV = noninvasive ventilation; PEEP = positive end-expiratory pressure; PICU = pediatric ICU; PIP = peak inspiratory pressure; RDAI = Respiratory Distress Assessment Index; RR = respiratory rate; RSV = respiratory syncytial virus; Sao2 = arterial oxygen saturation; Spo2 = oxygen saturation as measured by pulse oximetry; tCO2 = transcutaneous CO2.

a 

Comparison is before and after commencing intervention.

b 

Comparison is between intervention and control groups.

Seven prospective observational studies reported physiologic outcomes after starting CPAP in infants with bronchiolitis: one of nasal CPAP in 10 infants (none subsequently required invasive ventilation),44 one of nasal CPAP in 69 infants (12 [17%] required invasive ventilation),33 one of nasal CPAP in 12 infants (none required invasive ventilation),32 one of nasal CPAP as a modality of respiratory support for 54 infants during transport to an intensive care facility (five [9%] required mechanical ventilation within 24 h of arrival),34 one of nasal CPAP to deliver a heliox mixture (70% helium, 30% oxygen) to 15 infants (one [6.7%] required mechanical ventilation),40 one of CPAP administered through a helmet interface to deliver a heliox mixture (70% helium, 30% oxygen) to eight infants (one [12.5%] required invasive ventilation),41 and one of CPAP administered through a helmet interface to deliver an air/oxygen blend to 23 infants (two [8.7%] required mechanical ventilation).42 These studies reported that the use of CPAP in infants with bronchiolitis appears to confer improvements in capillary Pco2, Fio2, respiratory rate, and heart rate, generally within a few hours. The magnitude of clinical response varies among these studies (respiratory rate improves by between 942 and 1744 breaths/min, Fio2 between 0.0742 and 0.15,32 and Pco2 between 0.8 kPa [6 mm Hg]42 and 2.0 kPa [6 and 15 mm Hg]32).

Other observational studies described that the introduction of CPAP coincides with reduced rates of admission to the pediatric ICU (PICU) or the need for intubation and mechanical ventilation. Over a 10-year period in one PICU, the use of CPAP (either nasally or by full face mask) increased by 2.8% per year, and the need for invasive ventilator support decreased by 1.4% per year.35 Of the infants treated initially with CPAP, 48 of 285 (16.8%) required subsequent invasive ventilation. One retrospective review described the rates of mechanical ventilation for bronchiolitis in a PICU over two consecutive winters.36 During the first winter, clinicians intubated and administered mechanical ventilation if they believed that an infant needed respiratory support, and during the second winter, clinicians used noninvasive ventilation (either CPAP or bilevel support) as first-level intervention. During the first season, 47 of 53 infants (89%) were intubated, and in the second season, noninvasive ventilation was tried in 15 of 27 infants (66.6%) (of whom two received CPAP and the rest bilevel support), and nine (33.3%) were intubated directly.

At best, observational studies such as these provide some indication, rather than direct evidence, that in some infants with bronchiolitis, nasal CPAP may be an alternative to mechanical ventilation. These retrospective and prospective observational studies differ not only in the method of CPAP delivery but also in the age of infants, severity of bronchiolitis, and the reporting of outcomes. Interpretation is also hindered by the absence of a control group, strict eligibility criteria, and a priori criteria for intubation and mechanical ventilation (ie, a definition of treatment failure for CPAP). There may also be some publication bias such that only studies finding positive results are reported.

CPAP has been compared with standard care in two RCTs (Table 2).52,53 Thia et al52 compared CPAP with usual care (face mask or low-flow nasal cannula) in a crossover study of 31 infants with bronchiolitis and capillary Pco2 > 6 kPa (45 mm Hg). The treatment phases lasted 12 h each with no washout period. Improvement in the primary outcome of a reduction in Pco2 between baseline and 12 h was statistically significant after CPAP therapy (−0.92 kPa [6.9 mm Hg] vs 0.04 kPa [0.3 mm Hg], P < .015); whether this represents a clinically relevant magnitude of change is unclear. Secondary outcomes, including respiratory rate, pulse rate, and length of stay, were not different between groups. The risks of bias in this study were that it was not blinded, analysis was per protocol rather than intention to treat (although only two infants, who were both randomized to standard care first, were withdrawn because of treatment failure), and results for all outcomes were not reported. Another important consideration is whether a crossover trial design, usually used in conditions that remain stable over the study period, is appropriate in bronchiolitis, which may progress or improve over 12 h. This design carries the risk of period and carryover effects between treatment periods, which may limit the validity of the study.

Table Graphic Jump Location
TABLE 2 ]  Randomized Controlled Trials Comparing CPAP or HFNC to Standard Therapy

RACS = Respiratory Assessment Change Score. See Table 1 legend for expansion of other abbreviations.

Milési et al53 compared nasal CPAP with low-flow cannula in 19 infants with severe RSV bronchiolitis. The primary outcome of clinical severity at 6 h, measured by modified Woods Clinical Asthma Score, showed statistically significant improvement in the CPAP group (−2.4 points from baseline vs −0.5 points, P = .03). Inspiratory muscle work measured through esophageal pressure recordings was also better in the CPAP group (P = .04), but respiratory rate, heart rate, and blood gas analysis were not different. The main risk of bias was that the identity of the interventions was not blinded, which is particularly relevant because the primary outcome measure involved subjective assessments. It is also important to note that this measure has not been validated as an outcome measure in infants with bronchiolitis requiring PICU admission, nor has its responsiveness over short time spans, such as 6 h been evaluated.56 It is also unclear whether the observed improvements in clinical score and inspiratory muscle effort represent an important change in clinical status or risk of requiring intubation.

In six studies, researchers attempted to identify factors that may predict failure of CPAP in bronchiolitis.33,35-37,39,45 Campion et al33 prospectively studied 69 infants receiving noninvasive ventilation (NIV) for bronchiolitis, of whom 12 subsequently required ventilation. Factors associated with failure of NIV were apneas (10 of 12 babies in whom NIV failed vs 21 of 57 babies who responded to NIV, P = .017), higher median Pco2 (80 mm Hg [10.6 kPa] vs 66 mm Hg [8.8 kPa], P = .013), and higher median Pediatric Risk of Mortality score at 24 h (15 vs 10, P = .006). In another prospective observational study,45 seven of 11 infants in whom CPAP failed were ex-preterm, and eight had a Pco2 > 8 kPa (60 mm Hg) before commencing CPAP. A retrospective notes review37 of 50 babies admitted to a high-dependency unit and requiring CPAP found that of the nine who subsequently required invasive ventilation, four were ex-preterm and one had Down syndrome, whereas another four had no underlying problems. A further retrospective study35 in 285 infants in the PICU requiring NIV, of whom 48 did not respond, did not find a single risk factor that predicted treatment failure but did report that the presence of at least one of prematurity, uncorrected congenital heart disease, or neuromuscular disease was associated with failure of NIV.

In a retrospective notes review, Lazner et al39 found that six of 61 infants with bronchiolitis failed to respond to CPAP and required invasive ventilation. The nonresponders had a significantly higher rate of bacterial coinfection (two of 16 nonresponders vs two of 52 responders, P = .045). The authors of another retrospective study36 in 27 babies in the PICU requiring NIV (either CPAP or bilevel positive airway pressure) identified five babies who subsequently required intubation, two of whom had bacterial pulmonary infection.

Most evidence for HFNC oxygen therapy has come from studies of premature infants with respiratory distress syndrome, often as an alternative to CPAP.57 Other studies describe its use in older children with other conditions such as pneumonia, neuromuscular disorders, and OSA58-62 or as a potential strategy to prevent extubation failure.63

Speculation exists about the mechanisms by which HFNC benefit infants with respiratory distress partly because the physiologic bases of this intervention are not yet completely understood. Potential mechanisms are that HFNC devices may be an effective way of delivering high concentrations of oxygen and may generate some PEEP. Until further robust, physiologic studies are conducted to evaluate mechanisms of HFNC action, these benefits can only be considered theoretical, and the effects of these on clinical outcomes can only be speculated.

HFNCs can deliver higher concentrations of oxygen than low-flow nasal cannulae. Usually, low-flow nasal cannulae are used to deliver unblended oxygen supplied from a wall or cylinder. By the time the oxygen reaches the respiratory conducting zones, it is diluted for two main reasons. First, the delivered flow rates, which are limited to about 2 L/min if the oxygen is neither warmed nor humidified, are less than the infant’s intrinsic nasal flow rate. This means that infants breathe room air around the cannulae with each breath, and this mixes with the oxygen to reduce the actual Fio2. Second, the inspired gas mixes with exhaled CO2 in the respiratory conducting zones, which reduces the concentration of oxygen available to the alveoli with the next breath.64

HFNCs can deliver higher concentrations of oxygen because of factors relating to the properties of the delivered gas, the high flow with which it is administered (usually 1-2 L/kg/min vs up to 2 L/min from low-flow cannulae), and the interface between device and patient.64 HFNC devices deliver a precise blend of oxygen that is humidified and warmed to near body temperature, which enables high-flow rates tolerable to patients. The cannulae themselves tend to sit higher in the nose, which helps to overcome dilutional effects caused by the infant’s intrinsic nasal flow rate. The higher flow rates may also help to wash out CO2 from the nasal and pharyngeal passages, which may increase the concentration of oxygen available for delivery from conducting to respiratory zones at the start of each inhalation.

Conflicting evidence exists about whether the high flows used in HFNC devices generate clinically significant PEEP. Some research has suggested that the levels of PEEP, even under experimental conditions, are too low to be clinically significant,65-68 but other studies have suggested that higher PEEP can be generated under optimal conditions.46,49,69 Heterogeneity between these results may reflect the various ways of approximating distending pressure (pharyngeal, nasopharyngeal, or esophageal), differing methodologies among studies, variations in whether infants had open or closed mouths, and the size of nasal cannulae used.70 It is also important to remember that any PEEP generated cannot be regulated or monitored. A recognized complication of both low-flow nasal cannula and HFNC systems lacking a valve to release excess pressure is that PEEP may inadvertently reach dangerously high levels, such as 12 or even 18 cm H2O, with risk of air leak.71-73 There also is a case report of a neonate with sporadic pneumocephalus, pneumoorbitis, and subcutaneous scalp edema.74

Despite these issues, HFNCs are conceptually an attractive intervention in bronchiolitis. A problematic aspect of respiratory failure in bronchiolitis is hypoxemia, so the ability to deliver high concentrations of oxygen comfortably and accurately may prevent the need for intubation and mechanical ventilation. The devices are usually well-tolerated,46-48,54,75 which is important because if infants with bronchiolitis become distressed or uncomfortable, the efficiency of breathing is reduced. Anecdotal reports suggested that nursing staff perceive HFNC devices to be easier to set up than CPAP and may be less likely to cause nasal trauma.76-78 The humidification of the oxygen may also have beneficial effects on the airway milieu because moistening thick secretions may reduce mucus plugging and atelectasis.11

Observational studies describing the physiologic effects of HFNC in infants with bronchiolitis are summarized in Table 1. In one prospective study in 27 infants with moderate to severe bronchiolitis in a general pediatric ward, the authors reported a sustained increase in median oxygen saturation as measured by pulse oximetry from 89% on air and 96% on nasal cannula oxygen 1 h before initiation of HFNC therapy to 97% to 99%, respectively, at each measurement up to 48 h after commencing HFNC.47 The authors also reported a decrease in median end-tidal CO2 from 36 mm Hg (4.8 kPa) to 29 to 30 mm Hg (3.9-4 kPa) after commencing HFNC at a flow in liters per minute equivalent to the child’s weight in kilograms + 1. In a prospective observational study of the use of HFNC in the PICU, physiologic changes in 14 infants with bronchiolitis were reported.51 The authors described that the mean respiratory rate of infants with bronchiolitis decreased from 60 to 54 breaths/min after initiation of HFNC oxygen at a flow of 2 L/kg/min. They also described reductions in esophageal pressures and diaphragmatic activity as an estimate of the work of breathing in babies with bronchiolitis.

Two prospective studies described changes in nasopharyngeal and esophageal pressures as an estimate of distending pressure after initiation of HFNC oxygen in infants with bronchiolitis.46,49 One study in 25 patients set in a pediatric ED found that nasopharyngeal pressures of babies with bronchiolitis increased linearly with the flow rate (at an estimated 0.45 cm H2O for every 1 L/min increase in flow rate) and that this was most accelerated with flows up to 6 L/min.46 The other study in 21 infants with bronchiolitis in the PICU reported an increase in mean pharyngeal pressure from 0.2 cm H2O on HFNC at a flow of 1 L/min to 4 cm H2O at a flow of 7 L/min.49

A retrospective notes review in 115 infants with bronchiolitis in the PICU in 2 consecutive years before and after the introduction of HFNC to the unit found that the availability of HFNC was associated with a significantly reduced rate of intubation from 23% before the introduction to 9% the year after.48 Another retrospective case notes review compared 34 infants with bronchiolitis in the PICU in 2 consecutive years.50 Infants in the first year received CPAP, and those in the second year received HFNC oxygen at a flow rate of up to 3 L/kg/min (up to a maximum of 8 L/min). The authors found a significant decrease in mean maximal respiratory rates and Fio2 and a significant increase in mean pH in both groups after commencement of noninvasive respiratory support but found no difference between the groups in either of these parameters.

HFNC was evaluated in two RCTs in infants with bronchiolitis (Table 2).54,55 In one, a pilot study not reported in full, HFNC was compared with headbox oxygen in 19 infants with moderately severe bronchiolitis.54 This study demonstrated significant differences in the primary outcome of oxygen saturation at 8 h (results not presented numerically). However, this may reflect the fact that Fio2 was also higher in the HFNC group at this time point and remained higher at 12 and 24 h. No difference was demonstrated in the time taken to wean to nasal cannula oxygen or air in time to establish feeds or in length of hospital stay.

The other RCT compared HFNC with nebulized hypertonic saline in infants with moderate bronchiolitis.55 This study did not demonstrate any difference in respiratory distress, as measured by the Respiratory Assessment Change Score, between the two groups at any time point during the 36 h after randomization. Secondary outcomes measured were comfort score, length of stay, and rates of PICU admission, none of which were demonstrated to be improved by HFNC compared with hypertonic saline. The study was at low risk of bias, other than the absence of blinding, but it is important to note that there are limits to the validity of the Respiratory Assessment Change Score as an outcome measure in bronchiolitis.79

One study aimed to identify predictors of failure of HFNC oxygen in infants with bronchiolitis admitted to the PICU by retrospectively reviewing the case notes of 113 babies treated with HFNC at the time of admission with flow rates between 3 and 8 L/min80; 92 responders to HFNC therapy and 21 nonresponders were identified. Predictors of HFNC failure were a lower pH (7.26 vs 7.30 in nonresponders and responders, respectively) and higher Pco2 (8.9 kPa [67 mm Hg] vs 7.5 kPa [56 mm Hg]) before commencing treatment, higher Pediatric Risk of Mortality scores (median, 5.0 vs 1.0), a lower respiratory rate before commencing treatment (mean, 44 breaths/min vs 54 breaths/min), and a lack of change in respiratory rate after initiation of HFNC. Lower mean weight (4.2 kg vs 5.0 kg in nonresponders and responders, respectively) and weight-for-corrected-age percentiles (25 kg vs 40 kg) were also found to predict failure to respond to HFNC.

Further research is required to evaluate CPAP and HFNC regarding important clinical and cost-effectiveness outcomes in both high- and low-income settings and with various levels of care. Randomized head-to-head comparisons of CPAP, HFNC, and headbox oxygen would help clinicians to understand whether these modalities of respiratory support actually reduce the need for PICU admission and if they do, which is the most effective. These studies should be conducted in infants with severe respiratory distress or failure and should measure important outcomes such as the need for PICU admission and other clinical end points reflecting respiratory distress. Multicenter collaboration would be needed to accrue the required number of subjects.

Certain aspects of the design and reporting of RCTs in bronchiolitis should be standardized. Consensus should be reached about which outcomes to include in the studies and how these should be measured.81 Core outcome sets, which are a minimum set of outcomes that should be measured and reported in all clinical trials in a given condition, have been implemented in RCTs in other clinical areas but not as yet in bronchiolitis.82 Consensus can be reached using structured methods, such as the Delphi technique, and guidance is available for how this can be achieved.83 To standardize studies aiming to measure distending pressure generated by HFNC and CPAP devices, research should first identify whether pharyngeal, nasopharyngeal, or esophageal pressure is the most appropriate outcome to measure. Reports of RCTs should also include clear descriptions of the definitions of bronchiolitis, criteria used to determine severity and which infants are believed to require intubation (ie, a definition of treatment failure), and criteria for PICU as well as hospital discharge.

Regarding respiratory support modalities in clinical settings, unanswered questions still remain about which patient interface is the most effective and best tolerated and what flow rates and PEEP to set for HFNC and CPAP devices, respectively, and which weaning strategies are most appropriate. Such research could be conducted before head-to-head RCTs to compare these interventions when used most effectively. Adequate allocation concealment is important because blinding may not always be feasible.

CPAP and HFNC are conceptually attractive modalities for infants with severe bronchiolitis and may improve physiologic and clinical outcomes associated with respiratory distress and failure. Both deliver high concentrations of warmed, humidified oxygen precisely and accurately. PEEP generated by CPAP devices may also help to overcome airway resistance and atelectasis, and HFNC may also generate significant distending pressure, but the current evidence around this is conflicting. Observational studies have suggested that CPAP and HFNC reduce the need for intensive care, but no evidence from RCTs has demonstrated this to be the case. High-quality RCTs using standardized methodology should be conducted to identify whether HFNC and CPAP do in fact confer benefits on important clinical outcomes for infants with bronchiolitis.

Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Other contributions: The authors thank Richard McBride, MBChB, for drawing the illustrations.

HFNC

high-flow nasal cannula

NIV

noninvasive ventilation

PEEP

positive end-expiratory pressure

PICU

pediatric ICU

RCT

randomized controlled trial

RSV

respiratory syncytial virus

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Kristensen K, Hjuler T, Ravn H, Simões EA, Stensballe LG. Chronic diseases, chromosomal abnormalities, and congenital malformations as risk factors for respiratory syncytial virus hospitalization: a population-based cohort study. Clin Infect Dis. 2012;54(6):810-817. [CrossRef] [PubMed]
 
Ralston SL, Lieberthal AS, Meissner HC, et al; American Academy of Pediatrics. Clinical practice guideline: the diagnosis, management, and prevention of bronchiolitis. Pediatrics. 2014;134(5):e1474-e1502. [CrossRef] [PubMed]
 
Hartling L, Fernandes RM, Bialy L, et al. Steroids and bronchodilators for acute bronchiolitis in the first two years of life: systematic review and meta-analysis. BMJ. 2011;342:d1714. [CrossRef] [PubMed]
 
Gadomski AM, Scribani MB. Bronchodilators for bronchiolitis. Cochrane Database Syst Rev. 2014;6:CD001266. [PubMed]
 
Zhang L, Mendoza-Sassi RA, Wainwright C, Klassen TP. Nebulised hypertonic saline solution for acute bronchiolitis in infants. Cochrane Database Syst Rev. 2013;7:CD006458. [PubMed]
 
Barben J, Kuehni CE. Hypertonic saline for acute viral bronchiolitis: take the evidence with a grain of salt. Eur Respir J. 2014;44(4):827-830. [CrossRef] [PubMed]
 
Mansbach JM, Piedra PA, Stevenson MD, et al; MARC-30 Investigators. Prospective multicenter study of children with bronchiolitis requiring mechanical ventilation. Pediatrics. 2012;130(3):e492-e500. [CrossRef] [PubMed]
 
Kuluz JW, McLaughlin GE, Gelman B, et al. The fraction of inspired oxygen in infants receiving oxygen via nasal cannula often exceeds safe levels. Respir Care. 2001;46(9):897-901. [PubMed]
 
Javouhey E, Pouyau R, Massenavette B. Pathophysiology of acute respiratory failure in children with bronchiolitis and effect of CPAP.. In:Esquinas AM., ed. Noninvasive Ventilation in High-Risk Infections and Mass Casualty Events. Vienna, Austria: Springer; 2014:233-249.
 
Beasley JM, Jones SEF. Continuous positive airway pressure in bronchiolitis. Br Med J (Clin Res Ed). 1981;283(6305):1506-1508. [CrossRef] [PubMed]
 
Cahill J, Moore KP, Wren WS. Nasopharyngeal continuous positive airway pressure in the management of bronchiolitis. Ir Med J. 1983;76(4):191-192. [PubMed]
 
Cambonie G, Milési C, Jaber S, et al. Nasal continuous positive airway pressure decreases respiratory muscles overload in young infants with severe acute viral bronchiolitis. Intensive Care Med. 2008;34(10):1865-1872. [CrossRef] [PubMed]
 
Campion A, Huvenne H, Leteurtre S, et al. Non-invasive ventilation in infants with severe infection presumably due to respiratory syncytial virus: feasibility and failure criteria [in French]. Arch Pediatr. 2006;13(11):1404-1409. [CrossRef] [PubMed]
 
Fleming PF, Richards S, Waterman K, et al. Use of continuous positive airway pressure during stabilisation and retrieval of infants with suspected bronchiolitis. J Paediatr Child Health. 2012;48(12):1071-1075. [CrossRef] [PubMed]
 
Ganu SS, Gautam A, Wilkins B, Egan J. Increase in use of non-invasive ventilation for infants with severe bronchiolitis is associated with decline in intubation rates over a decade. Intensive Care Med. 2012;38(7):1177-1183. [CrossRef] [PubMed]
 
Javouhey E, Barats A, Richard N, Stamm D, Floret D. Non-invasive ventilation as primary ventilatory support for infants with severe bronchiolitis. Intensive Care Med. 2008;34(9):1608-1614. [CrossRef] [PubMed]
 
Kallappa C, Ninan T. Role of nasal continuous positive airway pressure (NCPAP) in bronchiolitis – experience from a large district general hospital in United Kingdom [abstract]. Acta Paediatr. 2008;97(suppl 459):46. [PubMed]
 
Larrar S, Essouri S, Durand P, et al. Effects of nasal continuous positive airway pressure ventilation in infants with severe acute bronchiolitis [in French]. Arch Pediatr. 2006;13(11):1397-1403. [CrossRef] [PubMed]
 
Lazner MR, Basu AP, Klonin H. Non-invasive ventilation for severe bronchiolitis: analysis and evidence. Pediatr Pulmonol. 2012;47(9):909-916. [CrossRef] [PubMed]
 
Martinón-Torres F, Rodríguez-Núñez A, Martinón-Sánchez JM. Nasal continuous positive airway pressure with heliox in infants with acute bronchiolitis. Respir Med. 2006;100(8):1458-1462. [CrossRef] [PubMed]
 
Mayordomo-Colunga J, Medina A, Rey C, Concha A, Los Arcos M, Menéndez S. Helmet-delivered continuous positive airway pressure with heliox in respiratory syncytial virus bronchiolitis. Acta Paediatr. 2010;99(2):308-311. [PubMed]
 
Milési C, Ferragu F, Jaber S, et al. Continuous positive airway pressure ventilation with helmet in infants under 1 year. Intensive Care Med. 2010;36(9):1592-1596. [CrossRef] [PubMed]
 
Pirret AM, Sherring CL, Tai JA, Galbraith NE, Patel R, Skinner SM. Local experience with the use of nasal bubble CPAP in infants with bronchiolitis admitted to a combined adult/paediatric intensive care unit. Intensive Crit Care Nurs. 2005;21(5):314-319. [CrossRef] [PubMed]
 
Soong WJ, Hwang B, Tang RB. Continuous positive airway pressure by nasal prongs in bronchiolitis. Pediatr Pulmonol. 1993;16(3):163-166. [CrossRef] [PubMed]
 
Vamvakiti E, Saha A, Linney M. Use of nasal CPAP in infants with bronchiolitis in the south of England: a prospective, multicenter, observational study [poster]. Pediatr Res. 2010;68:261. [CrossRef]
 
Arora B, Mahajan P, Zidan MA, Sethuraman U. Nasopharyngeal airway pressures in bronchiolitis patients treated with high-flow nasal cannula oxygen therapy. Pediatr Emerg Care. 2012;28(11):1179-1184. [CrossRef] [PubMed]
 
Bressan S, Balzani M, Krauss B, Pettenazzo A, Zanconato S, Baraldi E. High-flow nasal cannula oxygen for bronchiolitis in a pediatric ward: a pilot study. Eur J Pediatr. 2013;172(12):1649-1656. [CrossRef] [PubMed]
 
McKiernan C, Chua LC, Visintainer PF, Allen H. High flow nasal cannulae therapy in infants with bronchiolitis. J Pediatr. 2010;156(4):634-638. [CrossRef] [PubMed]
 
Milési C, Baleine J, Matecki S, et al. Is treatment with a high flow nasal cannula effective in acute viral bronchiolitis? A physiologic study [published correction appears in Intensive Care Med. 2013;39(6):1170]. Intensive Care Med. 2013;39(6):1088-1094. [CrossRef] [PubMed]
 
Metge P, Grimaldi C, Hassid S, et al. Comparison of a high-flow humidified nasal cannula to nasal continuous positive airway pressure in children with acute bronchiolitis: experience in a pediatric intensive care unit. Eur J Pediatr. 2014;173(7):953-958. [CrossRef] [PubMed]
 
Pham TM, O’Malley L, Mayfield S, Martin S, Schibler A. The effect of high flow nasal cannula therapy on the work of breathing in infants with bronchiolitis [published online ahead of print May 21, 2014]. Pediatr Pulmonol. doi:10.1002/ppul.23060.
 
Thia LP, McKenzie SA, Blyth TP, Minasian CC, Kozlowska WJ, Carr SB. Randomised controlled trial of nasal continuous positive airways pressure (CPAP) in bronchiolitis. Arch Dis Child. 2008;93(1):45-47. [CrossRef] [PubMed]
 
Milési C, Matecki S, Jaber S, et al. 6 cmH2O continuous positive airway pressure versus conventional oxygen therapy in severe viral bronchiolitis: a randomized trial. Pediatr Pulmonol. 2013;48(1):45-51. [CrossRef] [PubMed]
 
Hilliard TN, Archer N, Laura H, et al. Pilot study of vapotherm oxygen delivery in moderately severe bronchiolitis. Arch Dis Child. 2012;97(2):182-183. [CrossRef] [PubMed]
 
Bueno Campaña M, Olivares Ortiz J, Notario Muñoz C, et al. High flow therapy versus hypertonic saline in bronchiolitis: randomised controlled trial. Arch Dis Child. 2014;99(6):511-515. [CrossRef] [PubMed]
 
Duarte-Dorado DM, Madero-Orostegui DS, Rodriguez-Martinez CE, Nino G. Validation of a scale to assess the severity of bronchiolitis in a population of hospitalized infants. J Asthma. 2013;50(10):1056-1061. [CrossRef] [PubMed]
 
Wilkinson D, Andersen C, O’Donnell CP, De Paoli AG. High flow nasal cannula for respiratory support in preterm infants. Cochrane Database Syst Rev. 2011;5(5):CD006405. [PubMed]
 
Lee JH, Rehder KJ, Williford L, Cheifetz IM, Turner DA. Use of high flow nasal cannula in critically ill infants, children, and adults: a critical review of the literature. Intensive Care Med. 2013;39(2):247-257. [CrossRef] [PubMed]
 
Spentzas T, Minarik M, Patters AB, Vinson B, Stidham G. Children with respiratory distress treated with high-flow nasal cannula. J Intensive Care Med. 2009;24(5):323-328. [CrossRef] [PubMed]
 
Schibler A, Pham TM, Dunster KR, et al. Reduced intubation rates for infants after introduction of high-flow nasal prong oxygen delivery. Intensive Care Med. 2011;37(5):847-852. [CrossRef] [PubMed]
 
Wing R, James C, Maranda LS, Armsby CC. Use of high-flow nasal cannula support in the emergency department reduces the need for intubation in pediatric acute respiratory insufficiency. Pediatr Emerg Care. 2012;28(11):1117-1123. [CrossRef] [PubMed]
 
McGinley B, Halbower A, Schwartz AR, Smith PL, Patil SP, Schneider H. Effect of a high-flow open nasal cannula system on obstructive sleep apnea in children. Pediatrics. 2009;124(1):179-188. [CrossRef] [PubMed]
 
Woodhead DD, Lambert DK, Clark JM, Christensen RD. Comparing two methods of delivering high-flow gas therapy by nasal cannula following endotracheal extubation: a prospective, randomized, masked, crossover trial. J Perinatol. 2006;26(8):481-485. [CrossRef] [PubMed]
 
Dysart K, Miller TL, Wolfson MR, Shaffer TH. Research in high flow therapy: mechanisms of action. Respir Med. 2009;103(10):1400-1405. [CrossRef] [PubMed]
 
Lampland AL, Plumm B, Meyers PA, Worwa CT, Mammel MC. Observational study of humidified high-flow nasal cannula compared with nasal continuous positive airway pressure. J Pediatr. 2009;154(2):177-182. [CrossRef] [PubMed]
 
Saslow JG, Aghai ZH, Nakhla TA, et al. Work of breathing using high-flow nasal cannula in preterm infants. J Perinatol. 2006;26(8):476-480. [CrossRef] [PubMed]
 
Essouri S, Durand P, Chevret L, et al. Optimal level of nasal continuous positive airway pressure in severe viral bronchiolitis. Intensive Care Med. 2011;37(12):2002-2007. [CrossRef] [PubMed]
 
Lavizzari A, Veneroni C, Colnaghi M, et al. Respiratory mechanics during NCPAP and HHHFNC at equal distending pressures. Arch Dis Child Fetal Neonatal Ed. 2014;99(4):F315-F320. [CrossRef] [PubMed]
 
Sreenan C, Lemke RP, Hudson-Mason A, Osiovich H. High-flow nasal cannulae in the management of apnea of prematurity: a comparison with conventional nasal continuous positive airway pressure. Pediatrics. 2001;107(5):1081-1083. [CrossRef] [PubMed]
 
Haq I, Gopalakaje S, Fenton AC, McKean MC, J O’Brien C, Brodlie M. The evidence for high flow nasal cannula devices in infants. Paediatr Respir Rev. 2014;15(2):124-134. [PubMed]
 
Sivieri EM, Gerdes JS, Abbasi S. Effect of HFNC flow rate, cannula size, and nares diameter on generated airway pressures: an in vitro study. Pediatr Pulmonol. 2013;48(5):506-514. [CrossRef] [PubMed]
 
Locke RG, Wolfson MR, Shaffer TH, Rubenstein SD, Greenspan JS. Inadvertent administration of positive end-distending pressure during nasal cannula flow. Pediatrics. 1993;91(1):135-138. [PubMed]
 
Hegde S, Prodhan P. Serious air leak syndrome complicating high-flow nasal cannula therapy: a report of 3 cases. Pediatrics. 2013;131(3):e939-e944. [CrossRef] [PubMed]
 
Jasin LR, Kern S, Thompson S, Walter C, Rone JM, Yohannan MD. Subcutaneous scalp emphysema, pneumo-orbitis and pneumocephalus in a neonate on high humidity high flow nasal cannula. J Perinatol. 2008;28(11):779-781. [CrossRef] [PubMed]
 
Klingenberg C, Pettersen M, Hansen EA, et al. Patient comfort during treatment with heated humidified high flow nasal cannulae versus nasal continuous positive airway pressure: a randomised cross-over trial. Arch Dis Child Fetal Neonatal Ed. 2014;99(2):F134-F137. [CrossRef] [PubMed]
 
Manley BJ, Owen LS, Doyle LW, et al. High-flow nasal cannulae in very preterm infants after extubation. N Engl J Med. 2013;369(15):1425-1433. [CrossRef] [PubMed]
 
Fernandez-Alvarez JR, Gandhi RS, Amess P, Mahoney L, Watkins R, Rabe H. Heated humidified high-flow nasal cannula versus low-flow nasal cannula as weaning mode from nasal CPAP in infants ≤28 weeks of gestation. Eur J Pediatr. 2014;173(1):93-98. [CrossRef] [PubMed]
 
de Klerk A. Humidified high-flow nasal cannula: is it the new and improved CPAP? Adv Neonatal Care. 2008;8(2):98-106. [CrossRef] [PubMed]
 
Fernandes RM, Plint AC, Terwee CB, Klassen TP, Offringa M, van der Lee JH. Measurement properties of RDAI and RACS and their suitability as outcome measures in bronchiolitis trials. Eur Respir J. 2014;44(suppl 58):P1256.
 
Abboud PA, Roth PJ, Skiles CL, Stolfi A, Rowin ME. Predictors of failure in infants with viral bronchiolitis treated with high-flow, high-humidity nasal cannula therapy. Pediatr Crit Care Med. 2012;13(6):e343-e349. [CrossRef] [PubMed]
 
Sinha IP, Altman DG, Beresford MW, et al; StaR Child Health Group. Standard 5: selection, measurement, and reporting of outcomes in clinical trials in children. Pediatrics. 2012;129(suppl 3):S146-S152. [CrossRef] [PubMed]
 
Sinha I, Jones L, Smyth RL, Williamson PR. A systematic review of studies that aim to determine which outcomes to measure in clinical trials in children. PLoS Med. 2008;5(4):e96. [CrossRef] [PubMed]
 
Sinha IP, Smyth RL, Williamson PR. Using the Delphi technique to determine which outcomes to measure in clinical trials: recommendations for the future based on a systematic review of existing studies. PLoS Med. 2011;8(1):e1000393. [CrossRef] [PubMed]
 

Figures

Figure Jump LinkFigure 1 –  Mechanisms of respiratory failure in bronchiolitis and possible actions of CPAP and HFNC. Intraluminal mucus and debris cause airway obstruction (A) and increased resistance (B). Warmed, humidified oxygen can reduce intraluminal mucus (A1), and positive end-expiratory pressure (PEEP) from CPAP (and possibly HFNC) might help to overcome resistance (B1). Intraluminal obstruction causes atelectasis (C). Increased PEEP prevents atelectasis (C1). Increased interstitial edema limits oxygen transport to blood, contributing to hypoxemic respiratory failure (D). CPAP and HFNC are efficient methods of delivering high oxygen concentrations to the lower airways (D1), which may overcome this. All these mechanisms cause respiratory muscle fatigue (E). Overcoming airway resistance (A1 and B1), reducing atelectasis (C1), and increasing oxygen delivery to the blood (D1) can help to reduce this respiratory muscle fatigue (E1). Although primarily a small airways disease, increased respiratory efforts can cause upper airway collapse in infants (F), and PEEP may help to reduce this (F1). HFNC = high-flow nasal cannula.Grahic Jump Location

Tables

Table Graphic Jump Location
TABLE 1 ]  Observational Studies Describing the Use of CPAP and HFNC in Bronchiolitis

EDIN = Échelle Douleur Inconfort Nouveau-Né (neonatal pain and discomfort scale); ETT = endotracheal tube; HDU = high-dependency unit; HFNC = high-flow nasal cannula; HR = heart rate; LOS = length of stay; m-WCAS = Modified Wood Clinical Asthma Score; NIV = noninvasive ventilation; PEEP = positive end-expiratory pressure; PICU = pediatric ICU; PIP = peak inspiratory pressure; RDAI = Respiratory Distress Assessment Index; RR = respiratory rate; RSV = respiratory syncytial virus; Sao2 = arterial oxygen saturation; Spo2 = oxygen saturation as measured by pulse oximetry; tCO2 = transcutaneous CO2.

a 

Comparison is before and after commencing intervention.

b 

Comparison is between intervention and control groups.

Table Graphic Jump Location
TABLE 2 ]  Randomized Controlled Trials Comparing CPAP or HFNC to Standard Therapy

RACS = Respiratory Assessment Change Score. See Table 1 legend for expansion of other abbreviations.

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Gadomski AM, Scribani MB. Bronchodilators for bronchiolitis. Cochrane Database Syst Rev. 2014;6:CD001266. [PubMed]
 
Zhang L, Mendoza-Sassi RA, Wainwright C, Klassen TP. Nebulised hypertonic saline solution for acute bronchiolitis in infants. Cochrane Database Syst Rev. 2013;7:CD006458. [PubMed]
 
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Mansbach JM, Piedra PA, Stevenson MD, et al; MARC-30 Investigators. Prospective multicenter study of children with bronchiolitis requiring mechanical ventilation. Pediatrics. 2012;130(3):e492-e500. [CrossRef] [PubMed]
 
Kuluz JW, McLaughlin GE, Gelman B, et al. The fraction of inspired oxygen in infants receiving oxygen via nasal cannula often exceeds safe levels. Respir Care. 2001;46(9):897-901. [PubMed]
 
Javouhey E, Pouyau R, Massenavette B. Pathophysiology of acute respiratory failure in children with bronchiolitis and effect of CPAP.. In:Esquinas AM., ed. Noninvasive Ventilation in High-Risk Infections and Mass Casualty Events. Vienna, Austria: Springer; 2014:233-249.
 
Beasley JM, Jones SEF. Continuous positive airway pressure in bronchiolitis. Br Med J (Clin Res Ed). 1981;283(6305):1506-1508. [CrossRef] [PubMed]
 
Cahill J, Moore KP, Wren WS. Nasopharyngeal continuous positive airway pressure in the management of bronchiolitis. Ir Med J. 1983;76(4):191-192. [PubMed]
 
Cambonie G, Milési C, Jaber S, et al. Nasal continuous positive airway pressure decreases respiratory muscles overload in young infants with severe acute viral bronchiolitis. Intensive Care Med. 2008;34(10):1865-1872. [CrossRef] [PubMed]
 
Campion A, Huvenne H, Leteurtre S, et al. Non-invasive ventilation in infants with severe infection presumably due to respiratory syncytial virus: feasibility and failure criteria [in French]. Arch Pediatr. 2006;13(11):1404-1409. [CrossRef] [PubMed]
 
Fleming PF, Richards S, Waterman K, et al. Use of continuous positive airway pressure during stabilisation and retrieval of infants with suspected bronchiolitis. J Paediatr Child Health. 2012;48(12):1071-1075. [CrossRef] [PubMed]
 
Ganu SS, Gautam A, Wilkins B, Egan J. Increase in use of non-invasive ventilation for infants with severe bronchiolitis is associated with decline in intubation rates over a decade. Intensive Care Med. 2012;38(7):1177-1183. [CrossRef] [PubMed]
 
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Abboud PA, Roth PJ, Skiles CL, Stolfi A, Rowin ME. Predictors of failure in infants with viral bronchiolitis treated with high-flow, high-humidity nasal cannula therapy. Pediatr Crit Care Med. 2012;13(6):e343-e349. [CrossRef] [PubMed]
 
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