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Continuous positive airway pressure (CPAP) for acute

bronchiolitis in children (Review)

Jat KR, Mathew JL

This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library
2015, Issue 1
http://www.thecochranelibrary.com

Continuous positive airway pressure (CPAP) for acute bronchiolitis in children (Review)
Copyright 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
TABLE OF CONTENTS
HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
SUMMARY OF FINDINGS FOR THE MAIN COMPARISON . . . . . . . . . . . . . . . . . . . 3
BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
Figure 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
Figure 3. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
Figure 4. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
Figure 5. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
Figure 6. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
AUTHORS CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
Analysis 1.1. Comparison 1 Proportion of patients requiring mechanical ventilation, Outcome 1 Proportion of patients
requiring mechanical ventilation. . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
Analysis 2.1. Comparison 2 Clinical improvements, Outcome 1 Change in respiratory rate from start to end of
intervention. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
Analysis 2.2. Comparison 2 Clinical improvements, Outcome 2 Change in oxygen saturation (SpO2). . . . . . 24
Analysis 2.3. Comparison 2 Clinical improvements, Outcome 3 Change in partial pressure of carbon dioxide from start to
end of intervention (mmHg). . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
Analysis 2.4. Comparison 2 Clinical improvements, Outcome 4 Duration of hospital stay (days). . . . . . . . 25
APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
DIFFERENCES BETWEEN PROTOCOL AND REVIEW . . . . . . . . . . . . . . . . . . . . . 29
NOTES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29

Continuous positive airway pressure (CPAP) for acute bronchiolitis in children (Review) i
Copyright 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
[Intervention Review]

Continuous positive airway pressure (CPAP) for acute


bronchiolitis in children

Kana R Jat1 , Joseph L Mathew2


1 Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India. 2 Department of Pediatrics, Advanced Pediatrics

Centre, Post Graduate Institute of Medical Education and Research, Chandigarh, India

Contact address: Kana R Jat, Department of Pediatrics, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, Delhi,
110029, India. drkanaram@gmail.com. drkanaram@yahoo.co.in.

Editorial group: Cochrane Acute Respiratory Infections Group.


Publication status and date: New, published in Issue 1, 2015.
Review content assessed as up-to-date: 17 April 2014.

Citation: Jat KR, Mathew JL. Continuous positive airway pressure (CPAP) for acute bronchiolitis in children. Cochrane Database of
Systematic Reviews 2015, Issue 1. Art. No.: CD010473. DOI: 10.1002/14651858.CD010473.pub2.

Copyright 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

ABSTRACT
Background
Acute bronchiolitis is one of the most frequent causes of emergency department visits and hospitalisation in infants. There is no
specific treatment for bronchiolitis except for supportive therapy. Continuous positive airway pressure (CPAP) is supposed to widen the
peripheral airways of the lung, allowing deflation of over-distended lungs in bronchiolitis. The increase in airway pressure also prevents
the collapse of poorly supported peripheral small airways during expiration. In observational studies, CPAP is found to be beneficial in
acute bronchiolitis.
Objectives
To assess the efficacy and safety of CPAP compared to no CPAP or sham CPAP in infants and children up to three years of age with
acute bronchiolitis.
Search methods
We searched CENTRAL (2014, Issue 3), MEDLINE (1946 to April week 2, 2014), EMBASE (1974 to April 2014), CINAHL (1981
to April 2014) and LILACS (1982 to April 2014).
Selection criteria
We considered randomised controlled trials (RCTs), quasi-RCTS, cross-over RCTs and cluster-RCTs evaluating the effect of CPAP in
children with acute bronchiolitis.
Data collection and analysis
Two review authors independently assessed study eligibility, extracted data using a structured proforma, analysed the data and performed
meta-analyses.
Main results
We included two studies with a total of 50 participants under 12 months of age. In one study there was a high risk of bias for incomplete
outcome data and selective reporting, and both studies had an unclear risk of bias for several domains including random sequence
generation. The effect of CPAP on the need for mechanical ventilation in children with acute bronchiolitis was uncertain due to
Continuous positive airway pressure (CPAP) for acute bronchiolitis in children (Review) 1
Copyright 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
imprecision around the effect estimate (two RCTs, 50 participants; risk ratio (RR) 0.19, 95% CI 0.01 to 3.63; low quality evidence).
Neither trial measured our other primary outcome of time to recovery. One trial found that CPAP significantly improved respiratory
rate compared with no CPAP (one RCT, 19 participants; mean difference (MD) -5.70 breaths per minute, 95% CI -9.30 to -2.10),
although the other study reported no difference between groups with no numerical data to pool. Change in arterial oxygen saturation
was measured in only one trial and the results were imprecise (one RCT, 19 participants; MD -1.70%, 95% CI -3.76 to 0.36). The effect
of CPAP on the change in partial pressure of carbon dioxide (pCO2 ) was also imprecise (two RCTs, 50 participants; MD -2.62 mmHg,
95% CI -5.29 to 0.05; low quality evidence). Duration of hospital stay was similar in both of the groups (two RCTs, 50 participants;
MD 0.07 days, 95% CI -0.36 to 0.50; low quality evidence). Both trials reported no cases of pneumothorax and there were no deaths
in either study. Change in partial pressure of oxygen (pO2 ), hospital admission rate (from emergency department to hospital), duration
of emergency department stay, need for intensive care unit admission, local nasal effects and shock were not measured in either study.
Authors conclusions
The effect of CPAP in children with acute bronchiolitis is uncertain due to the limited evidence available. Larger trials with adequate
power are needed to evaluate the effect of CPAP in children with acute bronchiolitis.

PLAIN LANGUAGE SUMMARY


Usefulness of continuous positive airway pressure (CPAP) for acute bronchiolitis in children
Review question
We reviewed the usefulness of continuous positive airway pressure (CPAP) for acute bronchiolitis in children.
Background
Bronchiolitis is an inflammation of the small airways of the lung and is one of the most common causes of emergency department
visits in young children. There are a lack of standard treatments for bronchiolitis. Continuous positive airway pressure (CPAP) is the
application of positive pressure to the airways of spontaneously breathing patients and it keeps the airways open so it may be useful in
reversing abnormalities in the airways in bronchiolitis. We wanted to discover whether CPAP is better or worse than standard treatments
for acute bronchiolitis in children.
Study characteristics
The evidence is current to April 2014. Two small randomised controlled trials (RCTs) enrolling 50 participants under 12 months of
age with a diagnosis of bronchiolitis were included in the review. One of the included studies was funded by the Clinical Research
Department of a University Hospital Centre; the other study did not report on the funding source.
Key results
Data were available for the following outcomes, but the results of the analyses were not precise enough to draw conclusions about them:
need for mechanical ventilation, respiratory rate, change in arterial oxygen saturation and change in partial pressure of carbon dioxide
(pCO2 ). Duration of hospital stay appeared to be similar whether CPAP was used or not. There were no cases of pneumothorax or
death in either study. The studies did not measure the following outcomes: time to recovery, change in partial pressure of oxygen (pO2 ),
hospital admission rate (from emergency department to hospital), duration of emergency department stay, need for intensive care unit
admission, local nasal effects and shock.
Quality of the evidence
The evidence was of low quality regarding the need of mechanical ventilation, removal of carbon dioxide from the lungs and duration
of hospital stay. Overall, there is a lack of evidence to recommend using CPAP in children with acute bronchiolitis.

Continuous positive airway pressure (CPAP) for acute bronchiolitis in children (Review) 2
Copyright 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Copyright 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Continuous positive airway pressure (CPAP) for acute bronchiolitis in children (Review) S U M M A R Y O F F I N D I N G S F O R T H E M A I N C O M P A R I S O N [Explanation]

Continuous positive airway pressure (CPAP) compared to standard treatment for acute bronchiolitis in children

Patient or population: children with acute bronchiolitis


Settings: paediatric emergency and paediatric intensive care unit
Intervention: continuous positive airway pressure (CPAP)
Comparison: standard treatment

Outcomes Illustrative comparative risks* (95% CI) Relative effect No. of participants Quality of the evidence Comments
(95% CI) (studies) (GRADE)

Assumed risk Corresponding risk

Standard treatment Continuous positive air-


way pressure (CPAP)

Proportion of patients Study population RR 0.19 50


requiring mechanical (0.01 to 3.63) (2 studies) low1,2
ventilation 83 per 1000 16 per 1000
Observation (1 to 302)
Follow-up: 5 to 10 days
Moderate

67 per 1000 13 per 1000


(1 to 243)

Change in partial pres- The mean change in par- 50


sure of carbon dioxide tial pressure of carbon (2 studies) low1,2
from start to end of in- dioxide from start to end
tervention (mmHg) of intervention (mmHg)
Arterial blood gas analy- in the intervention groups
sis was
2.62 lower
(5.29 lower to 0.05
higher)
3
Copyright 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Continuous positive airway pressure (CPAP) for acute bronchiolitis in children (Review)

Duration of hospital stay The mean duration of 50


(days) hospital stay (days) in the (2 studies) low1,2
Observation intervention groups was
0.07 higher
(0.36 lower to 0.5 higher)

Time to recovery Study population Not estimable 0 See comment


Hours (03 )
See comment See comment

Moderate

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (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).
CI: confidence interval; RR: risk ratio

GRADE Working Group grades of evidence


High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.
1 There were participants who did not complete the intervention in one trial and one outcome described in the methods section was not
reported in the same trial.
2 The confidence interval is wide.
3
Data were not reported for time to recovery in the included trials.
4
BACKGROUND been associated with some adverse effects, which may include lo-
cal and systemic effects, for example, nasal mucosal damage, nasal
excoriation, scarring, pressure necrosis and nasal septum distor-
tion (Lee 2002; Robertson 1996), aspiration secondary to gastric
Description of the condition insufflation (Kiciman 1998), pneumothorax (de Bie 2002), and a
decrease in cardiac output due to impaired pulmonary blood flow.
Acute bronchiolitis is one of the most frequent causes of emer-
gency department visits and hospitalisation in infants (Deshpande
2003; Handforth 2000). Bronchiolitis (inflammation of the small
airways in the lung) is predominantly a viral disease and usually How the intervention might work
affects infants and children younger than three years of age. It is
mostly caused by respiratory syncytial virus (RSV) (CDC 2010). In bronchiolitis the peripheral airways are most severely affected
About 2% to 3% of all infants require hospitalisation due to bron- by inflammation. In infants with acute bronchiolitis expiratory re-
chiolitis in the USA (Meissner 2009). Bronchiolitis occurs more sistance is found to be greater than inspiratory resistance suggest-
frequently in male infants who are not breast fed and who live in ing dynamic narrowing of the airways on expiration (Wohl 1969).
crowded conditions (Meates-Dennis 2005). Acute bronchiolitis is associated with increased thoracic gas vol-
Bronchiolitis typically presents with viral symptoms (sneezing, ume (air trapping) and total pulmonary resistance, and decreased
rhinorrhoea and fever), which gradually progress to paroxysmal dynamic compliance (Phelan 1968). Initially infants compensate
cough, wheezing, respiratory distress and irritability. Chest find- for the increased physiological dead space by increasing their res-
ings are non-specific and include wheezing, with or without fine piratory rate resulting in increased minute volume. Gradually they
crackles. Although not required for diagnosis, chest X-ray may becomes exhausted and minute volume falls with increase in par-
reveal hyperinflated lungs with patchy atelectasis. About 10% to tial pressure of carbon dioxide (pCO2 ) and hypoxaemia. From
15% of patients hospitalised with bronchiolitis respond poorly to here, the infant may improve with oxygen supplementation or
treatment and require intensive care management. Further, nearly may progress to respiratory failure.
half of these develop respiratory failure and need mechanical ven- When CPAP is applied it increases the functional residual capac-
tilation (Navas 1992). Although uncommon, bronchiolitis may ity of lungs, which results in enlargement of the diameter of al-
cause mortality, which ranges from 0.5% to 2% (Kabir 2003; Levy most all airways including the peripheral airways. The widening
1997). The mortality rate is higher in low-income countries. of the peripheral airways allows deflation of over-distended lungs
The management of bronchiolitis mainly includes supportive mea- in bronchiolitis. The increase in airway pressure also prevents the
sures like adequate fluid intake, antipyretics and humidified oxy- collapse of poorly supported peripheral small airways during ex-
gen supplementation if hypoxia is present (Davison 2004). Neb- piration. CPAP has been used in bronchiolitis and benefits have
ulised adrenaline (Hartling 2011a; Hartling 2011b) and hyper- been noted in observational studies (Beasley 1981; Soong 1993).
tonic nebulised saline (Zhang 2013) have been found to be ben- One of the advantages is that it may prevent the need for mechan-
eficial in acute bronchiolitis. Other therapeutic options, such ical ventilation in infants with acute bronchiolitis.
as corticosteroids (Fernandes 2013), antibiotics (Spurling 2011),
bronchodilators (Gadomski 2010), heliox inhalation therapy (Liet
2010), chest physiotherapy (Roqu i Figuls 2012), nebulised re- Why it is important to do this review
combinant human deoxyribonuclease (Merkus 2001; Nasr 2001),
ribavirin (Ventre 2007) and steam inhalation (Umoren 2011), Acute bronchiolitis is a common clinical condition affecting in-
have been tried with no definitive benefit in bronchiolitis. fants and young children, yet no specific treatment is available
except for supportive therapy. CPAP is often used for its manage-
ment on an empiric basis (i.e. based on personal experience with-
out good evidence from literature). We aim to assess the role of
Description of the intervention CPAP for this condition and a systematic review is best suited for
the purpose.
Continuous positive airway pressure (CPAP) is the application of
positive pressure to the airways of spontaneously breathing patients
throughout the respiratory cycle (Duncan 1986). It keeps the air-
ways open. CPAP may be applied to infants using nasal prongs
(NCPAP), nasopharyngeal tube (NP-CPAP) or infant nasal mask OBJECTIVES
(NM-CPAP). It is administered with a commercially available cir-
cuit used in conjunction with a continuous flow source, or a ven- To assess the efficacy and safety of CPAP compared to no CPAP or
tilator. CPAP devices may include the function of providing a sham CPAP in infants and children up to three years of age with
heated and humidified flow to the patient. The use of CPAP has acute bronchiolitis.

Continuous positive airway pressure (CPAP) for acute bronchiolitis in children (Review) 5
Copyright 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
METHODS Search methods for identification of studies

Electronic searches
Criteria for considering studies for this review
We searched the Cochrane Central Register of Controlled Trials
(CENTRAL 2014, Issue 3) (accessed 17 April 2014), which in-
cludes the Acute Respiratory Infections (ARI) Groups Specialised
Types of studies
Register, MEDLINE (1946 to week 2, 2014), EMBASE (1974 to
Randomised controlled trials (RCTs) and quasi-RCTS. We also April 2014), CINAHL (1981 to April 2014) and LILACS (1982
included cross-over RCTs and cluster-RCTs. to April 2014).
We used the search strategy described in Appendix 1 to search
CENTRAL and MEDLINE. We combined the MEDLINE search
Types of participants
strategy with the Cochrane Highly Sensitive Search Strategy for
Children up to three years of age with acute bronchiolitis. Bron- identifying randomised trials in MEDLINE: sensitivity-maximis-
chiolitis is usually diagnosed clinically, therefore studies including ing version (2008 revision); Ovid format (Lefebvre 2011). We
children with a clinical diagnosis of bronchiolitis were eligible for adapted the search strategy to search EMBASE (Appendix 2),
inclusion. We included all infants, whether RSV-positive, negative CINAHL (Appendix 3) and LILACS (Appendix 4). We did not
or with unconfirmed RSV status. use any date, language or publication restrictions.

Types of interventions Searching other resources


We included CPAP with any pressure level and delivered by any We searched ClinicalTrials.gov and the WHO International Clin-
type of device, by any mode (nasal prongs, face mask, etc.) and for ical Trials Registry Platform (ICTRP) for completed and ongoing
any duration of time, compared to no CPAP or sham CPAP. We trials (latest search 17 April 2014). We independently reviewed the
included all studies with CPAP applied at any time after presenta- reference lists of the included studies to identify additional studies,
tion. We excluded studies that included high-flow nasal cannulae if any. One review author (KRJ) contacted corresponding authors
(HFNC) as there is a separate review evaluating such trials (Beggs of included trials to ask about any additional ongoing RCTs or
2014). We included trials where both arms received similar man- unpublished trials.
agement in all other respects.

Data collection and analysis


Types of outcome measures

Selection of studies
Primary outcomes
Two review authors (KRJ, JLM) independently assessed the title
1. Need for mechanical ventilation.
and abstract of studies obtained through the search strategy to
2. Time to recovery (as defined by the included trial).
identify relevant studies for the review. We retrieved the full text
of the selected potentially relevant studies. We independently as-
Secondary outcomes sessed the full text of identified relevant studies for inclusion as per
the criteria mentioned. One review author (KRJ) corresponded
1. Change in respiratory rate. with investigators, where appropriate, to clarify study eligibility if
2. Change in arterial oxygen saturation. required. We listed excluded studies with reason(s) for exclusion.
3. Change in arterial pCO2 and partial pressure of oxygen We resolved any disagreements by discussion.
(pO2 ).
4. Hospital admission rate (from emergency department to
hospital). Data extraction and management
5. Duration of emergency department stay. Two review authors (KRJ, JLM) independently extracted data us-
6. Duration of hospital stay. ing a pre-defined data collection form in accordance with the
7. Need for intensive care unit admission. Cochrane Handbook for Systematic Reviews of Interventions (Higgins
8. Adverse events, for example, local nasal effects, 2011), which included the following data: source, eligibility, meth-
pneumothorax and shock. ods, participants and settings, interventions, outcomes, results,
9. Mortality. adverse effects and miscellaneous (funding source of the study, or

Continuous positive airway pressure (CPAP) for acute bronchiolitis in children (Review) 6
Copyright 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
potential conflicts of interest). We resolved any disagreements by in the numbers randomised and the numbers analysed in each
discussion. treatment group.

Assessment of risk of bias in included studies Assessment of heterogeneity


Two review authors (KRJ, JLM) assessed risk of bias in the in- We assessed clinical and methodological heterogeneity before
cluded studies using the criteria described in the Cochrane Hand- pooling. We compared inclusion and exclusion criteria among the
book for Systematic Reviews of Interventions (Higgins 2011). This included studies to assess clinical heterogeneity. We carried out
included a judgement for each specific feature of the study as low assessment for statistical heterogeneity visually by looking at forest
risk, high risk or unclear risk of bias (unclear means either plots, using a Chi2 test and using the I2 statistic. Using the Chi
lack of information or uncertainty over the potential for bias). 2 test, a low P value of < 0.1 (or a large Chi2 test statistic relative

The specific features were random sequence generation, allocation to its degree of freedom) provided evidence of heterogeneity of
concealment, blinding of participants/personnel and blinding of intervention effects. We interpreted the value of the I2 statistic
outcome assessors, incomplete outcome data, selective reporting as follows: 0% to 40%, heterogeneity might not be important; >
and other sources of bias. We created a Risk of bias graph figure 40% to 60%, moderate heterogeneity; > 60% to 80%, substantial
and Risk of bias summary figure using RevMan 2014. heterogeneity and > 80% to 100%, considerable heterogeneity.

Measures of treatment effect Assessment of reporting biases


We analysed dichotomous outcomes by calculating the risk ratio There was an insufficient number of included studies to assess
(RR). We expressed continuous outcome data as mean differences publication bias by funnel plot. We will assess publication bias by
(MD). We expressed the overall results with a 95% confidence funnel plots in RevMan 2014, if sufficient numbers of included
interval (CI). studies become available in future updates.

Unit of analysis issues Data synthesis


We included RCTs, quasi-RCTs, cross-over RCTs and cluster- We carried out meta-analyses using RevMan 2014. We used a
RCTs. In cross-over trials, we considered data from the first study fixed-effect model for pooled data analysis. We used a random-
period for meta-analysis. If we find any cluster-RCTs in future up- effects meta-analysis if there was important (more than 40%) sta-
dates, we will meta-analyse them using the generic inverse variance tistical heterogeneity among studies. We created a Summary of
method in RevMan 2014. We will add standard parallel-group findings (SOF) table using GRADEPro 2008 software. We in-
trials into the same generic inverse variance meta-analysis. cluded the primary outcomes, change in partial pressure of pCO2
and duration of hospital stay in the SOF table. Sufficient data for
hospital admission rate and adverse events were not available for
Dealing with missing data inclusion in the SOF table.
We took the following steps for missing data.
1. We contacted the trial investigators requesting that the
missing data be provided. Subgroup analysis and investigation of heterogeneity
2. We performed sensitivity analyses to assess the effects of any There were an insufficient number of included studies to perform
assumptions, if they were made. subgroup analysis. We will perform subgroup analyses for the fol-
3. We addressed the potential impact of missing data on the lowing groups if sufficient data become available in future updates.
findings of the review in the Discussion section. 1. CPAP with oxygen and CPAP with heliox.
4. We calculated the standard deviation (SD) from study 2. RSV-positive and RSV-negative participants.
statistics (for example, CI, standard errors, t values, P values or F 3. Different pressure levels of CPAP (below 6, 6 to 10, and >
values) for missing SDs for continuous outcome data. If SD 10 cm water level (H2 O)).
calculation was still not possible, then we imputed from other 4. Method of CPAP, via nasal prongs or with a face mask.
studies in the meta-analysis as per the Cochrane Handbook for 5. Duration of CPAP (< 12 hours, 12 to 24 hours, > 24 hours).
Systematic Reviews of Interventions recommendations (Higgins 6. Trials with no CPAP and sham CPAP as comparator.
2011). 7. RCTs and cross-over RCTs.
We extracted data to allow an intention-to-treat (ITT) analysis, We will investigate statistical heterogeneity by performing sub-
where possible, which aims to include all participants randomised group analyses and sensitivity analysis to determine the possible
into a trial irrespective of what happened subsequently. We calcu- reason(s), for example, due to low quality trials. There was no
lated and reported the loss to follow-up if there was a discrepancy considerable heterogeneity in the two included trials.

Continuous positive airway pressure (CPAP) for acute bronchiolitis in children (Review) 7
Copyright 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Sensitivity analysis Description of studies
There were an insufficient number of included studies to perform All the results are based on published data only. We sent emails
sensitivity analysis. We will perform sensitivity analyses to test the to the authors of the included studies to request additional details
robustness of the results if a sufficient number of trials are found but received no additional information.
in future updates.
1. Repeating the meta-analysis after the exclusion of studies
with inadequate concealment of allocation. Results of the search
2. Repeating the meta-analysis after the exclusion of studies in We retrieved a total 275 records from the electronic searches. We
which the outcome evaluation was not blinded. identified one additional record through the World Health Orga-
3. Repeating the meta-analysis imputing missing data as best nization (WHO) International Clinical Trials Registry Platform
possible and worst possible outcome(s). (ICTRP) search. After excluding five duplicates, we screened a total
4. Comparing the difference in pooled analysis results by of 271 records (title and abstracts) for eligibility (Figure 1). Out of
using a fixed-effect model and a random-effects model. these, we excluded 263 and retrieved the full text of the remaining
eight articles to assess them for eligibility. We excluded six full-text
articles for the reasons given in Characteristics of excluded studies
and included two trials for qualitative and quantitative synthesis
RESULTS (Milsi 2013; Thia 2008) (Figure 1).

Continuous positive airway pressure (CPAP) for acute bronchiolitis in children (Review) 8
Copyright 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Figure 1. Study flow diagram.

Continuous positive airway pressure (CPAP) for acute bronchiolitis in children (Review) 9
Copyright 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
ing use of nasal prongs, requiring immediate invasive ventilation,
Included studies
and pCO2 > 12 kPa.
Milsi 2013 used nCPAP of 6 cmH2 O with the Infant Flow Ven-
We included two studies, enrolling 50 participants. Details of these
tilator via a mask connected to a twin injector nozzle fixed to the
studies are provided in the Characteristics of included studies ta-
patient by a specially designed bonnet in the experimental group
ble. One study from France was a parallel-group RCT (Milsi
and the control group received a heated and humidified air/oxygen
2013), whereas the other from the UK was a randomised cross-
mixture delivered through a nasal cannula. Thia 2008 used stan-
over study (Thia 2008). We used only the first period of this cross-
dard treatment (minimal handling, intravenous fluids and oxygen
over trial for this review. Both trials were conducted at single cen-
by nasal prongs or face mask) plus nasal CPAP for 12 hours fol-
tres. We summarised the extracted data from the included studies
lowed by standard treatment alone for the next 12 hours in the
in Appendix 5.
experimental group and or (b) standard treatment alone for 12
Milsi 2013 included infants below six months of age and Thia
hours followed by standard treatment plus nasal CPAP for the
2008 enrolled participants below 12 months old. The mean age of
next 12 hours in the control group. The outcome measures for
participants in the CPAP group was 6.8 0.9 and 10.92 41.33
both of the included studies are provided in the Characteristics of
weeks in the trials by Milsi 2013 and Thia 2008 respectively. The
included studies table.
respective mean age of participants in the control group was 8.2
1.7 and 10.5 48.93 weeks.
Milsi 2013 included only RSV-positive cases of bronchiolitis, Excluded studies
whereas in Thia 2008, 20 out of 31 cases of bronchiolitis were We excluded six studies for the reasons given in the Characteristics
RSV-positive. Milsi 2013 included participants who had severe of excluded studies table (Balanzat 2006; Chidini 2011; Hough
respiratory distress defined by a modified Woods clinical asthma 2011; Javouhey 2008; Smith 1993; Yaez 2008).
score (m-WCAS) > 4; no invasive or non-invasive ventilation, in-
cluding nasal continuous positive airway pressure (nCPAP), prior
to PICU admission; and who had no underlying cardiopulmonary
Risk of bias in included studies
or neuromuscular disease and no pneumothorax on chest radio- The Risk of bias assessment of the included studies for each cri-
graph. Thia 2008 enrolled participants with capillary pCO2 mea- terion is shown in the Characteristics of included studies table,
surements > 6 kPa and excluded patients with congenital heart dis- Risk of bias graph (Figure 2) and Risk of bias summary (Figure
ease, neuromuscular disease and mid-face dysmorphism prohibit- 3).

Figure 2. Risk of bias graph: review authors judgements about each risk of bias item presented as
percentages across all included studies.

Continuous positive airway pressure (CPAP) for acute bronchiolitis in children (Review) 10
Copyright 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Figure 3. Risk of bias summary: review authors judgements about each risk of bias item for each included
study.

Allocation
studies. Outcome assessors were blinded in Milsi 2013 and this
The method of random sequence generation was not mentioned in was not reported in Thia 2008.
either of the two included studies. Sequentially numbered, opaque
and sealed envelopes were used for allocation concealment in
Milsi 2013 and this was not reported in Thia 2008.

Incomplete outcome data


Blinding
Blinding of participants was not reported in Milsi 2013 and they There was no loss to follow-up in Milsi 2013 and two partici-
were not blinded to the intervention in Thia 2008. Blinding of pants did not complete the intervention in one arm and were not
health care providers was not described in either of the included included in the analysis in Thia 2008.

Continuous positive airway pressure (CPAP) for acute bronchiolitis in children (Review) 11
Copyright 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Selective reporting See: Summary of findings for the main comparison Continuous
Milsi 2013 reported all described outcomes, whereas Thia 2008 positive airway pressure (CPAP) compared to standard treatment
did not report data regarding one of the secondary outcomes (cap- for acute bronchiolitis in children
illary pH).
Primary outcomes
Other potential sources of bias
Thia 2008 did not report the source of funding. Small sample size
1. Need for mechanical ventilation
and under powering of both studies were also a source of bias,
although one study provided a basis for sample size calculation None of the participants in the study by Milsi 2013 required
(Milsi 2013). mechanical ventilation whereas two patients in the control group
(standard treatment first) in the study by Thia 2008 required me-
chanical ventilation, however the difference was not statistically
Effects of interventions significant (Analysis 1.1; Figure 4).

Figure 4. Forest plot of comparison: 1 Outcome measures between CPAP group and control group,
outcome: 1.1 Proportion of patients requiring mechanical ventilation.

2. Change in arterial oxygen saturation


2. Time to recovery (as defined by the included trial)
Neither of the included studies provided data regarding partici- Change in arterial oxygen saturation was not different between the
pants time to recovery. groups in the study by Milsi 2013 (Analysis 2.2) and data were
not available from the other study (Thia 2008).

Secondary outcomes

3. Change in arterial pCO2 and partial pressure of oxygen


1. Change in respiratory rate
(pO2 )
Data for change in respiratory rate from start to end of interven-
tion were available from one study (Milsi 2013) and it decreased Change in partial pressure of carbon dioxide (pCO2 ) was not dif-
more in the CPAP group (Analysis 2.1). There was no change in ferent in the CPAP group compared to the control group with a
respiratory rate between the groups in the study by Thia 2008, mean difference (MD) of -2.62 (95% confidence interval (CI) -
although it did not provide numerical values to allow pooling of 5.29 to 0.05) mmHg (Analysis 2.3; Figure 5). No data were avail-
the data. able for change in partial pressure of oxygen (pO2 ).

Continuous positive airway pressure (CPAP) for acute bronchiolitis in children (Review) 12
Copyright 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Figure 5. Forest plot of comparison: 2 Secondary outcomes, outcome: 2.3 Change in partial pressure of
carbon dioxide from start to end of intervention (mmHg).

4. Hospital admission rate (from emergency department to


hospital)
The hospital admission rate (from emergency department to hos-
pital) was not reported in the included trials.

5. Duration of emergency department stay


The duration of emergency department stay was not reported in
the included trials.

6. Duration of hospital stay


Duration of hospital stay was similar between the groups (Analysis
2.4; Figure 6).

Figure 6. Forest plot of comparison: 2 Secondary outcomes, outcome: 2.4 Duration of hospital stay (days).

9. Mortality
7. Need for intensive care unit admission

The need for intensive care unit admission was not reported in the There were no deaths in either of the studies.
included trials. The primary outcome in Milsi 2013 was a change in the modified
Woods clinical asthma score (m-WCAS) and this score decreased
in the CPAP group compared to the controls with value of -2.4
1.05 versus -0.5 1.3 (P value = 0.03). Milsi 2013 also evaluated
8. Adverse events, for example, local nasal effects,
inspiratory muscle work by calculating the pressure-time product
pneumothorax and shock
per breath (PTPinsp/breath) and per minute (PTPinsp/min) from
Data related to local nasal effects, pneumothorax and shock were the oesophageal pressure (Pes) recordings and PTPesinsp/breath
not reported in the included trials. and PTPesinsp/min deceased in the intervention group compared
Continuous positive airway pressure (CPAP) for acute bronchiolitis in children (Review) 13
Copyright 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
with the control condition with values of 9.7 5.7 versus 1.4 Potential biases in the review process
8.2 (P value = 0.04) and 666 402 versus 116 352 (P value =
The search strategy for this review was broad and it was performed
0.015), respectively.
by the Trials Search Co-ordinator of the Cochrane Acute Respira-
The quality of the evidence is summarised in Summary of findings
tory Infections (ARI) Group, thus it is unlikely that any relevant
for the main comparison.
study was missed. Two review authors carried out study selection,
data extraction and analysis independently. We judged many do-
mains of risk of bias as unclear for both of the included stud-
ies because of non-availability of data (Characteristics of included
studies), therefore it was difficult to assess risk of bias in the in-
DISCUSSION cluded studies accurately. Data were not available for many out-
comes and we did not get any replies from the trial authors. One
Summary of main results of the included studies was a cross-over trial where we used data
from the first part of trial for meta-analysis, which may decrease
This review evaluated the effects of continuous positive airway the power of the study (Thia 2008).
pressure (CPAP) for acute bronchiolitis in children. The results of
the review are summarised in Summary of findings for the main
comparison and Data and analyses. There was no difference in
the requirement for mechanical ventilation in either group. Nei- Agreements and disagreements with other
ther included trial reported any case of pneumothorax or other studies or reviews
significant adverse effects. Change in partial pressure of carbon Donlan 2011 conducted a systematic review of the use of CPAP
dioxide (pCO2 ) was no different in the CPAP group compared to in acute bronchiolitis where both randomised and observational
the control group. Duration of hospital stay was similar in both studies were included. This review reported that CPAP reduced
groups. There were insufficient data to draw any conclusions re- pCO2 , respiratory rate and modified Woods clinical asthma score
garding time to recovery, change in respiratory rate, change in arte- in acute bronchiolitis but the quality of the evidence was classified
rial oxygen saturation, change in partial pressure of oxygen (pO2 ), as low. The same review also concluded that there was no conclu-
hospital admission rate (from emergency department to hospital), sive evidence that CPAP reduces the need for intubation. In one of
duration of emergency department stay, need for intensive care the excluded studies (Chidini 2011), CPAP by helmet versus facial
unit admission, local nasal effects and shock. mask was compared in a randomised trial and it was concluded that
CPAP delivered by helmet was associated with increased success-
ful treatment, less sedation and sores, and a similar improvement
in oxygenation with respect to the facial mask in cases of acute
Overall completeness and applicability of
lung injury. In another excluded RCT, the authors compared non-
evidence
invasive ventilation (NIV) using inspiratory positive airway pres-
The total number of participants (50) in the included studies sure and expiratory positive airway pressure plus standard therapy
was small. If we want to detect a 20% difference in the primary (study group) to standard therapy (control group) in 50 children
outcome (need for mechanical ventilation) with 80% power, 88 with acute respiratory failure. NIV was associated with improve-
participants per group are required. Data were not available for ment in hypoxaemia and the signs and symptoms of acute respira-
most of the secondary outcomes. There was high risk of bias for two tory failure with protection from endotracheal intubation (Yaez
domains in one included trial (Thia 2008). Our review suggests 2008). A few observational studies have suggested that CPAP is
a lack of evidence of efficacy of CPAP for acute bronchiolitis in beneficial in children with acute viral bronchiolitis (Beasley 1981;
children. Cambonie 2008; Essouri 2011; Larrar 2006; McNamara 1997;
Soong 1993).

Quality of the evidence


There was low quality evidence for the outcomes presented in
AUTHORS CONCLUSIONS
Summary of findings for the main comparison. There was a high
risk of bias for two domains in one of the included studies (Thia
2008), as shown in Figure 2 and Figure 3. Neither of the included
Implications for practice
trials reported the method of random sequence generation. Data Several outcomes were not measured in the included studies, and
for one primary outcome and many of the secondary outcomes of where data were available the findings were not precise enough
our review were not reported in the included trials. to draw definite conclusions. Overall, there is lack of evidence in

Continuous positive airway pressure (CPAP) for acute bronchiolitis in children (Review) 14
Copyright 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
favour of or against the use of continuous positive airway pressure ACKNOWLEDGEMENTS
(CPAP) in children with acute bronchiolitis.

Implications for research


Larger trials with adequate power are needed to evaluate the effect We thank Sarah Thorning for writing the electronic search strat-
of CPAP in children with acute bronchiolitis. The timing and egy for the review. We would also like to acknowledge Liz Dooley
duration of CPAP application, level of CPAP, device for CPAP for supporting us in drafting the review. We also thank the follow-
application, and both clinical (including side effects, e.g. vomiting ing people for commenting on the draft review: Edward Grandi,
and aspiration) and laboratory outcomes need to be evaluated in Rodrigo Cavallazzi, Anne Greenough, Teresa Neeman and Lubna
future trials. Al-Ansary.

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Continuous positive airway pressure (CPAP) for acute bronchiolitis in children (Review) 17
Copyright 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
CHARACTERISTICS OF STUDIES

Characteristics of included studies [ordered by study ID]

Milsi 2013

Methods Prospective, randomised, monocentric study

Participants 19 infants < 6 months old and hospitalised in a PICU with bronchiolitis
Inclusion criteria: (1) RSV bronchiolitis confirmed by nasopharyngeal enzyme im-
munoassay; (2) severe respiratory distress defined by a modified Woods clinical asthma
score (m-WCAS) > 4; (3) no invasive or non-invasive ventilation, including nasal con-
tinuous positive airway pressure (nCPAP), prior to PICU admission; (4) no underlying
cardiopulmonary or neuromuscular disease and no pneumothorax on chest radiograph;
and (5) signed authorisation by the parents

Interventions Active intervention: nCPAP of 6 cm H2 O with the Infant Flow Ventilator via a mask
connected to a twin injector nozzle fixed to the patient by a specially designed bonnet
for 6 hours
Control: infants in the control group continued to receive a heated and humidified air/
oxygen mixture delivered through a nasal cannula, which allowed a maximum gas flow
of 2.5 L/min

Outcomes *Primary outcome measures: clinical score for respiratory distress at baseline (H0) and
at 6 hours (H6) after the beginning of the procedure. Respiratory distress was evaluated
with the modified Woods Clinical Asthma Score (m-WCAS)
Secondary outcome measures: clinical items: respiratory and cardiac rate, average blood
pressure at H0 and H6
Manometric: variation of oesophageal pressure at H0 and H6. Gasometric: minimal
FiO2 necessary to reach an oxygen saturation between 94% and 98%, transcutaneous
pCO2 , PaO2 /FiO2

Notes The study was conducted at the Pediatric Intensive Care Unit, CHU Montpellier, France
over 3 consecutive RSV epidemic periods, from November 2006 to March 2009
*Outcome measures were not clearly defined in the published trial; these are taken from
the registered trial at clinicaltrials.gov

Risk of bias

Bias Authors judgement Support for judgement

Random sequence generation (selection Unclear risk Random sequence generation is not men-
bias) tioned clearly. It is stated that participants
were were randomly assigned to 1 of the
interventions

Allocation concealment (selection bias) Low risk Sequentially numbered, opaque, sealed en-
velopes were used

Continuous positive airway pressure (CPAP) for acute bronchiolitis in children (Review) 18
Copyright 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Milsi 2013 (Continued)

Blinding of participants and personnel Unclear risk Not mentioned


(performance bias)
All outcomes

Blinding of outcome assessment (detection Low risk Outcome assessors were not aware of the
bias) allocated intervention
All outcomes

Incomplete outcome data (attrition bias) Low risk There was no loss to follow-up
All outcomes

Selective reporting (reporting bias) Low risk All defined outcomes were reported

Other bias Low risk Funding source: Clinical Research Depart-


ment of Montpellier University Hospital
Centre
Conflicts of interest: none

Thia 2008

Methods Randomised cross-over study

Participants 31 children less than 1 year of age with a clinical diagnosis of bronchiolitis and capillary
pCO2 measurements > 6 kPa
Excluded: congenital heart disease, neuromuscular disease and mid-face dysmorphism
prohibiting the use of nasal prongs, requiring immediate invasive ventilation, and pCO2
> 12 kPa

Interventions Eligible children were randomised to receive either (a) standard treatment plus nasal
CPAP for 12 h followed by standard treatment alone for the next 12 h or (b) standard
treatment alone for 12 h followed by standard treatment plus nasal CPAP for the next 12
h. Standard treatment was defined as minimal handling, intravenous fluids and oxygen
by nasal prongs or face mask. Nasal CPAP was applied using the Infant Flow System
with pressures of 5 to 6 cm H2 O

Outcomes Primary: change in pCO2 at 12 h of intervention


Secondary: capillary pH, respiratory rate, pulse rate and the need for invasive ventilatory
support

Notes The study was conducted over 3 winters from October 2002 to March 2005

Risk of bias

Bias Authors judgement Support for judgement

Random sequence generation (selection Unclear risk Not mentioned


bias)

Continuous positive airway pressure (CPAP) for acute bronchiolitis in children (Review) 19
Copyright 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Thia 2008 (Continued)

Allocation concealment (selection bias) Unclear risk Not mentioned

Blinding of participants and personnel Low risk It was not possible to blind the interventions because
(performance bias) of the obviously different methods of administration.
All outcomes Unblinding is less likely to introduce bias as the primary
outcome was objective in nature

Blinding of outcome assessment (detection Unclear risk Not mentioned


bias)
All outcomes

Incomplete outcome data (attrition bias) High risk 2 participants did not complete the intervention in 1
All outcomes arm and were not included in the analysis

Selective reporting (reporting bias) High risk One of the secondary outcomes (capillary pH), men-
tioned in the methods section, was not reported

Other bias Low risk Conflicts of interest: none

FiO2 : fractional inspired oxygen


h: hours
H2 O: pressure level measures as water column
kPa: kilopascal (a unit of pressure measurement)
m-WCAS: modified Woods clinical asthma score
nCPAP: nasal continuous positive airway pressure
PaO2 /FiO2 : partial pressure of oxygen/fractional inspired oxygen
pCO2 : partial pressure of carbon dioxide
pH: measurement unit for acidity
PICU: Paediatric Intensive Care Unit
RSV: respiratory syncytial virus

Characteristics of excluded studies [ordered by study ID]

Study Reason for exclusion

Balanzat 2006 This is not a randomised controlled trial; it is an observational study

Chidini 2011 Study compared different methods of CPAP delivery rather than CPAP versus no-CPAP

Hough 2011 Study compared different levels of CPAP produced by high-flow nasal prongs

Javouhey 2008 This is a retrospective study, not a randomised controlled trial

Continuous positive airway pressure (CPAP) for acute bronchiolitis in children (Review) 20
Copyright 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
(Continued)

Smith 1993 This is not a randomised controlled trial; it compared different levels of peak end expiratory pressure (PEEP) in
mechanically ventilated children with bronchiolitis

Yaez 2008 This is a study evaluating non-invasive ventilation rather than CPAP

CPAP: continuous positive airway pressure

Continuous positive airway pressure (CPAP) for acute bronchiolitis in children (Review) 21
Copyright 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
DATA AND ANALYSES

Comparison 1. Proportion of patients requiring mechanical ventilation

No. of No. of
Outcome or subgroup title studies participants Statistical method Effect size

1 Proportion of patients requiring 2 50 Risk Ratio (M-H, Fixed, 95% CI) 0.19 [0.01, 3.63]
mechanical ventilation

Comparison 2. Clinical improvements

No. of No. of
Outcome or subgroup title studies participants Statistical method Effect size

1 Change in respiratory rate from 1 19 Mean Difference (IV, Fixed, 95% CI) -5.7 [-9.30, -2.10]
start to end of intervention
2 Change in oxygen saturation 1 19 Mean Difference (IV, Fixed, 95% CI) -1.7 [-3.76, 0.36]
(SpO2 )
3 Change in partial pressure of 2 50 Mean Difference (IV, Fixed, 95% CI) -2.62 [-5.29, 0.05]
carbon dioxide from start to
end of intervention (mmHg)
4 Duration of hospital stay (days) 2 50 Mean Difference (IV, Fixed, 95% CI) 0.07 [-0.36, 0.50]

Analysis 1.1. Comparison 1 Proportion of patients requiring mechanical ventilation, Outcome 1 Proportion
of patients requiring mechanical ventilation.

Review: Continuous positive airway pressure (CPAP) for acute bronchiolitis in children

Comparison: 1 Proportion of patients requiring mechanical ventilation

Outcome: 1 Proportion of patients requiring mechanical ventilation

Study or subgroup CPAP group Control group Risk Ratio Weight Risk Ratio
n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

Mil si 2013 0/10 0/9 Not estimable

Thia 2008 0/16 2/15 100.0 % 0.19 [ 0.01, 3.63 ]

Total (95% CI) 26 24 100.0 % 0.19 [ 0.01, 3.63 ]


Total events: 0 (CPAP group), 2 (Control group)
Heterogeneity: not applicable
Test for overall effect: Z = 1.11 (P = 0.27)
Test for subgroup differences: Not applicable

0.005 0.1 1 10 200


Favours CPAP Favours control

Continuous positive airway pressure (CPAP) for acute bronchiolitis in children (Review) 22
Copyright 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Analysis 2.1. Comparison 2 Clinical improvements, Outcome 1 Change in respiratory rate from start to
end of intervention.
Review: Continuous positive airway pressure (CPAP) for acute bronchiolitis in children

Comparison: 2 Clinical improvements

Outcome: 1 Change in respiratory rate from start to end of intervention

Mean Mean
Study or subgroup CPAP Control Difference Weight Difference
N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI

Mil si 2013 10 -7 (4) 9 -1.3 (4) 100.0 % -5.70 [ -9.30, -2.10 ]

Total (95% CI) 10 9 100.0 % -5.70 [ -9.30, -2.10 ]


Heterogeneity: not applicable
Test for overall effect: Z = 3.10 (P = 0.0019)
Test for subgroup differences: Not applicable

-10 -5 0 5 10
Favours [CPAP] Favours [Control]

Continuous positive airway pressure (CPAP) for acute bronchiolitis in children (Review) 23
Copyright 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Analysis 2.2. Comparison 2 Clinical improvements, Outcome 2 Change in oxygen saturation (SpO2).

Review: Continuous positive airway pressure (CPAP) for acute bronchiolitis in children

Comparison: 2 Clinical improvements

Outcome: 2 Change in oxygen saturation (SpO2 )

Mean Mean
Study or subgroup CPAP Control Difference Weight Difference
N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI

Mil si 2013 10 0.7 (1) 9 2.4 (3) 100.0 % -1.70 [ -3.76, 0.36 ]

Total (95% CI) 10 9 100.0 % -1.70 [ -3.76, 0.36 ]


Heterogeneity: not applicable
Test for overall effect: Z = 1.62 (P = 0.11)
Test for subgroup differences: Not applicable

-4 -2 0 2 4
Favours CPAP Favours control

Analysis 2.3. Comparison 2 Clinical improvements, Outcome 3 Change in partial pressure of carbon
dioxide from start to end of intervention (mmHg).

Review: Continuous positive airway pressure (CPAP) for acute bronchiolitis in children

Comparison: 2 Clinical improvements

Outcome: 3 Change in partial pressure of carbon dioxide from start to end of intervention (mmHg)

Mean Mean
Study or subgroup CPAP Control Difference Weight Difference
N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI

Mil si 2013 10 -6 (2) 9 -4 (4) 85.1 % -2.00 [ -4.89, 0.89 ]

Thia 2008 16 -10.13 (10.26) 15 -3.98 (9.38) 14.9 % -6.15 [ -13.06, 0.76 ]

Total (95% CI) 26 24 100.0 % -2.62 [ -5.29, 0.05 ]


Heterogeneity: Chi2 = 1.18, df = 1 (P = 0.28); I2 =15%
Test for overall effect: Z = 1.92 (P = 0.054)
Test for subgroup differences: Not applicable

-10 -5 0 5 10
Favours CPAP Favours control

Continuous positive airway pressure (CPAP) for acute bronchiolitis in children (Review) 24
Copyright 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Analysis 2.4. Comparison 2 Clinical improvements, Outcome 4 Duration of hospital stay (days).

Review: Continuous positive airway pressure (CPAP) for acute bronchiolitis in children

Comparison: 2 Clinical improvements

Outcome: 4 Duration of hospital stay (days)

Mean Mean
Study or subgroup CPAP Control Difference Weight Difference
N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI

Mil si 2013 10 5 (0.5) 9 5 (0.5) 90.1 % 0.0 [ -0.45, 0.45 ]

Thia 2008 16 6.3 (2.3) 15 5.6 (1.5) 9.9 % 0.70 [ -0.66, 2.06 ]

Total (95% CI) 26 24 100.0 % 0.07 [ -0.36, 0.50 ]


Heterogeneity: Chi2 = 0.92, df = 1 (P = 0.34); I2 =0.0%
Test for overall effect: Z = 0.32 (P = 0.75)
Test for subgroup differences: Not applicable

-2 -1 0 1 2
Favours CPAP Favours control

APPENDICES

Appendix 1. MEDLINE (Ovid) search strategy


1 exp Bronchiolitis/
2 bronchiolit*.tw.
3 Bronchopneumonia/
4 bronchopneumon*.tw.
5 exp respiratory syncytial viruses/ or exp respiratory syncytial virus, human/
6 Respiratory Syncytial Virus Infections/
7 (respiratory syncytial virus* or rsv).tw.
8 or/1-7
9 Respiratory Therapy/
10 Respiration, Artificial/
11 positive-pressure respiration/ or continuous positive airway pressure/
12 (positive pressur* adj5 (ventilat* or respir* or breath* or airway*)).tw.
13 positiv* airway* pressur*.tw.
14 continuous distend* pressur*.tw.
15 positive end expiratory pressure.tw.
16 (ppv or cpap or ncpap or nm-cpap or np-cpap or peep).tw.
17 or/9-16
18 8 and 17

Continuous positive airway pressure (CPAP) for acute bronchiolitis in children (Review) 25
Copyright 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Appendix 2. EMBASE (Elsevier) search strategy
#14 *continuous distending pressure*:ab,ti 46*
#13 *ppv*:ab,ti OR *cpap*:ab,ti OR *ncpap*:ab,ti OR *nm-cpap*:ab,ti OR *np-cpap*:ab,ti 17000*
#12 *positive airway pressure*:ab,ti 6991*
#11 ((*positive pressure* OR *positive-pressure*) NEAR/5 (*ventilat** OR *respir** OR *breath** OR *airway**)):ab,ti 5253*
#10 *artificial ventilation*/de OR *positive end expiratory pressure*/de OR *cpap device*/de 78111*
#9 *#1* OR *#2* OR *#3* OR *#4* OR *#5* OR *#6* OR *#7* OR *#8**28466*
#8 *rsv*:ab,ti 7727*
#7 *respiratory syncytial virus*:ab,ti OR *respiratory syncytial viruses*:ab,ti 8252*
#6 *respiratory syncytial virus infection*/de 1132*
#5 *respiratory syncytial pneumovirus*/de 10173*
#4 *bronchopneumon**:ab,ti 2426*
#3 *bronchopneumonia*/de 3528*
#2 *bronchiolit**:ab,ti 8269*
#1 *bronchiolitis*/exp 11323*

Appendix 3. CINAHL (EBSCO) search strategy


S28 S18 AND S27 15
S27 S19 OR S20 OR S21 OR S22 OR S23 OR S24 OR S25 OR S26 189,818
S26 (MH Quantitative Studies) 8,622
S25 TI placebo* OR AB placebo* 20,274
S24 TI random* OR AB random* 100,950
S23 (MH Random Assignment) 29,181
S22 TI ((singl* or doubl* or tripl* or trebl*) N1 (blind* or mask*)) OR AB ((singl* or doubl* or tripl* or trebl*) N1 (blind* or mask*))
14,743
S21 TI clinic* N1 trial* OR AB clinic* N1 trial* 28,628
S20 PT clinical trial 50,141
S19 (MH Clinical Trials+) 113,828
S18 S9 AND S17 89
S17 S10 OR S11 OR S12 OR S13 OR S14 OR S15 OR S16 14,880
S16 TI (ppv or cpap or ncpap or nm-cpap or np-cpap or peep) OR AB (ppv or cpap or ncpap or nm-cpap or np-cpap or peep) 1,882
S15 TI positive end expiratory pressur* OR AB positive end expiratory pressur* 627
S14 TI continuous distending pressure OR AB continuous distending pressure 7
S13 TI positive airway* pressur* OR AB positive airway* pressur* 1,306
S12 TI ( (positive-pressure or positive pressure) N5 (ventilat* or respir* or breath* or airway*) ) OR AB ( (positive-pressure or positive
pressure) N5 (ventilat* or respir* or breath* or airway*) ) 2,199
S11 (MH Positive Pressure Ventilation) OR (MH Continuous Positive Airway Pressure) OR (MH Positive End-Expiratory
Pressure) 4,063
S10 (MH Respiratory Therapy) OR (MH Respiration, Artificial) 10,565
S9 S1 OR S2 OR S3 OR S4 OR S5 OR S6 OR S7 OR S8 1,924
S8 TI rsv OR AB rsv 478
S7 TI respiratory syncytial virus* OR AB respiratory syncytial virus*693
S6 (MH Respiratory Syncytial Virus Infections) 784
S5 (MH Respiratory Syncytial Viruses) 283
S4 TI bronchopneumon* OR AB bronchopneumon* 43
S3 (MH Bronchopneumonia) 40
S2 TI bronchiolit* OR AB bronchiolit* 748
S1 (MH Bronchiolitis+) 692

Continuous positive airway pressure (CPAP) for acute bronchiolitis in children (Review) 26
Copyright 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Appendix 4. LILACS (BIREME) search strategy
(mh:bronchiolitis OR bronchiolit* OR bronquiolitis OR bronquiolite OR mh:c08.127.446.135* OR mh:c08.381.495.146.135* OR
mh:c08.730.099.135* OR mh:bronchopneumonia OR bronchopneumon* OR bronconeumona OR broncopneumonia OR mh:
Respiratory Syncytial Viruses OR Virus Sincitiales Respiratorios OR Vrus Sinciciais Respiratrios OR Virus Sincitial Respira-
torio OR Virus Sincicial Respiratorio OR Virus Sinciciales Respiratorios OR Vrus Sincicial Respiratrio OR mh:Respiratory
Syncytial Virus, Human OR Virus Sincitial Respiratorio Humano OR Vrus Sincicial Respiratrio Humano OR mh:Respiratory
Syncytial Virus Infections OR Infecciones por Virus Sincitial Respiratorio OR Infeces por Vrus Respiratrio Sincicial OR
respiratory syncytial virus OR respiratory syncytial viruses OR rsv) AND (mh:Respiratory Therapy OR Terapia Respiratoria
OR mh:Respiration, Artificial OR Respiracin Artificial OR Respirao Artificial OR mh:Positive-Pressure Respiration OR
Respiracin con Presin Positiva OR Respirao com Presso Positiva OR Positive End-Expiratory Pressure OR mh:Continuous
Positive Airway Pressure OR Presin de las Vas Areas Positiva Contnua OR Presso Positiva Contnua nas Vias Areas OR
Airway Pressure Release Ventilation OR Ventilacin Liberadora de Presin de las Vas Areas OR Presso Positiva Contnua nas
Vias Respiratrias OR Ventilao com Liberao de Presso das Vias Areas OR vlpva OR Ventilao com Liberao de Presso
das Vias Respiratrias OR positive airway pressure OR continuous distending pressure OR ppv OR cpap OR ncpap OR nm-
cpap OR np-cpap OR peep OR positive pressure ventilation OR positive pressure respiration OR positive pressure breathing)
AND db:(LILACS) AND typeofstudy:(clinicaltrials)

Appendix 5. Data extraction from included studies

Study and Milsi 2013 Thia 2008


group

Parameters CPAP group Control group CPAP group Control group

Number of participants 10 9 16 15

Age in weeks (mean 6.8 0.9 8.2 1.7 10.9 41.3 10.5 8.9
SD)

No. of patients who re- 0 0 0 2


quired mechanical venti-
lation

Time to recovery (as de- NA NA NA NA


fined by the included
trial)

Change in respiratory -7 4 -1.3 4 NA NA


rate from baseline to end
of treatment

Change in arterial pCO2 -6 2 -4 4 -10.1 10.3 -3.9 9.4


from baseline to end of
treatment (mmHg)

Change in arterial pO2 NA NA NA NA


from baseline to end of
treatment

Continuous positive airway pressure (CPAP) for acute bronchiolitis in children (Review) 27
Copyright 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
(Continued)

Change 0.7 1 2.4 3 NA NA


in arterial oxygen satura-
tion from baseline to end
of treatment (%)

Hospital admission rate NA NA NA NA


(from emergency depart-
ment to
hospital)

Duration of emergency NA NA NA NA
department stay

Duration of hospital stay 5 0.5 5 0.5 6.3 2.3 5.6 1.5


(days) mean SD

No. of patients who NA NA NA NA


required intensive care
unit admission

No. of patients with local NA NA NA NA


nasal effects

No. of patients with 0 0 0 0


pneumothorax

No. of patients with NA NA NA NA


shock

Mortality 0 0 0 0

NA: not applicable


pCO2 : partial pressure of carbon dioxide
pO2 : partial pressure of oxygen
SD: standard deviation

CONTRIBUTIONS OF AUTHORS
Dr Jat (KRJ) designed and drafted the review.
Both the authors selected studies for review, independently extracted data and approved the final version of review
Dr Jat (KRJ) performed analysis. Dr Mathew (JLM) reviewed the analysis critically and suggested important intellectual input.

Continuous positive airway pressure (CPAP) for acute bronchiolitis in children (Review) 28
Copyright 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
DECLARATIONS OF INTEREST
Kana R Jat: no conflicts of interest.
Joseph L Mathew: no conflicts of interest.

SOURCES OF SUPPORT

Internal sources
Internet and library facility from Govt. Medical College Hospital, Chandigarh, India.

External sources
No sources of support supplied

DIFFERENCES BETWEEN PROTOCOL AND REVIEW


We included the primary outcomes, change in partial pressure of carbon dioxide (pCO2 ) and duration of hospital stay, in the Summary
of findings table. Sufficient data for hospital admission rate and adverse events were not available for inclusion in the Summary of
findings table as described in the protocol.

NOTES
None.

Continuous positive airway pressure (CPAP) for acute bronchiolitis in children (Review) 29
Copyright 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.