Expert Review of Respiratory Medicine

ISSN: 1747-6348 (Print) 1747-6356 (Online) Journal homepage: http://www.tandfonline.com/loi/ierx20

Therapeutic strategies for pediatric bronchiolitis

Matti Korppi

To cite this article: Matti Korppi (2018): Therapeutic strategies for pediatric bronchiolitis, Expert
Review of Respiratory Medicine, DOI: 10.1080/17476348.2019.1554439

To link to this article: https://doi.org/10.1080/17476348.2019.1554439

Accepted author version posted online: 29

Nov 2018.

Submit your article to this journal

Article views: 1

View Crossmark data

Full Terms & Conditions of access and use can be found at

http://www.tandfonline.com/action/journalInformation?journalCode=ierx20
Publisher: Taylor & Francis

Journal: Expert Review of Respiratory Medicine

DOI: 10.1080/17476348.2019.1554439
Therapeutic strategies for pediatric bronchiolitis

Matti Korppi1*

t
ip
1
Center for Child health Research,

cr
Tampere University and University Hospital, Finland

us
Arvo2 building, Tampere University,

33014, Tampere, Finland

an
M
*Corresponding author

Matti Korppi
ed

Center for Child health Research,

Tampere University and University Hospital, Finland

pt

Arvo2 building, Tampere University,

ce

33014, Tampere, Finland

Tel. +358-50-3186316
Ac

Email. matti.korppi@uta.fi
Abstract

Introduction: Bronchiolitis in infancy is the most common infectious reason for hospitalization of
infants without any chronic underlying illness.

Areas covered: This review focuses on the role of racemic epinephrine, systemic corticosteroids,
hypertonic saline and high-flow oxygen therapy (HFOT) in the treatment of infants with
bronchiolitis. Literature was searched from Pubmed covering the years 2009-2018 using the entries
of bronchiolitis or viral bronchiolitis, and epinephrine, adrenaline, racemic epinephrine, racemic

t
adrenaline, corticosteroids, hypertonic saline, high-flow oxygen therapy or high-flow oxygen

ip
cannula.

cr
Expert commentary: Many randomized controlled trials (RCT) have proved the ineffectiveness of
beta-agonists, anticholinergics and inhaled corticosteroids in infants with bronchiolitis. An RCT

us
from Norway suggested that there are bronchiolitis patients, who may benefit from well-timed, on-
demand inhalations of racemic epinephrine. Based on two RCTs from Qatar and USA, the benefits
an
of systemic steroids are marginal and need repeated doses, which increases the risk of adrenal
suppression. In new meta-analyses, inhalations of hypertonic saline did not substantially shorten the
stay in hospital for bronchiolitis. In two recent RCTs from Australia and New Zealand, HFOT with
M

warmed and humidified air-oxygen mixture was superior to traditional low-flow oxygenation.
HFOT is the only new and promising approach for treatment of infants with bronchiolitis.
ed

Key words: Bronchiolitis, Corticosteroids, Epinephrine, Hypertonic saline, Infant, Inhalation,

pt

High-flow oxygen therapy (HFOT)

ce
Ac
 1. Introduction

Bronchiolitis is the most common infectious reason for hospitalization in infancy. Every year,
mostly during respiratory syncytial virus (RSV) epidemics, 1-3% of infants aged less than 12
months visit outpatient clinics due to bronchiolitis [1, 2]. How many of them are hospitalized, how
many are treated on the pediatric wards and how many in the pediatric intensive care units (PICU),
depends on the age and disease severity, but also on the health care system of the country. The
needs of admissions to the PICUs are dependent on the facilities available on pediatric wards. In

t
Finland, only six percent of infants younger than 12 months hospitalized for bronchiolitis were

ip
admitted the PICU [3, 4].

cr
Bronchiolitis begins with upper respiratory symptoms followed by signs from lower airways, such
as tachypnea, chest retractions on inspection and wheezes or fine crackles on auscultation [1, 2].

us
Fever is mild to moderate but can also be absent. High fever in young infants raise the suspicion of
bacterial pneumonia or another invasive bacterial infection. Apneas may be present even as the first
an
sign of RSV bronchiolitis in young infants and in those who were born prematurely [5].

Age is the most important factor that effects to the etiology and clinical picture of bronchiolitis and
as a consequence, to the treatment strategies of infants with bronchiolitis. RSV predominates at the
M

age of less than 12 months and rhinoviruses thereafter, and subsequent wheezing episodes and later
asthma are more common after rhinovirus bronchiolitis [6]. Audible wheezes meaning bronchial
ed

obstruction become commoner by age, being present in most cases at the age approaching 24
months.
pt

In America, bronchiolitis is usually defined as the first episode of respiratory distress induced by
infection at the age of less than 24 months [2, 7]. In Europe, bronchiolitis is usually defined as the
ce

first episode of respiratory distress induced by infection at the age of less than 12 months with or
without wheezing, but necessarily without a previous wheezing history [7, 8]. The most typical
Ac

clinical picture of bronchiolitis can be seen in infants aged less than six months and the most severe
clinical picture in infants aged less than two to three months or in those who have been born
prematurely [1, 2]. When 144 hospitalizations for bronchiolitis in less than 12 months old infants
were retrospectively evaluated [7], 63% of the cases were considered misclassified. The most
common reason for misclassification was the history of prior episodes of wheezing, which was not
asked and taken into account [7].
This review mainly follows the European definition of bronchiolitis that is the first respiratory
distress induced by infection at less than 12 months of age. However, the interpretation of the
results published until now is challenging, since most studies have not reported data in infants aged
less than 12 months separately. Studies on infants who have a chronic underlying illness such as
cystic fibrosis or a severe neurologic, cardiologic or immunologic disease have been in most but not
in all studies excluded. Instead, data on infants who have been born prematurely but do not have
bronchopulmonary dysplasia have usually been included in the studies.

t
The cornerstones of bronchiolitis treatment are the monitoring of oxygenation, fluid intake and the

ip
work of breathing, and oxygen and fluid supplementation if needed. This review focuses on
systemic corticosteroids, inhaled racemic epinephrine and nebulized hypertonic saline in the

cr
treatment of infants with bronchiolitis. The review evaluates high-flow oxygen administration but

us
does not consider more invasive methods like mechanical ventilation or nasal continuous positive
airways pressure (CPAP). Currently, 19 vaccines and monoclonal antibodies against RSV are in
clinical trials, including three vaccines aimed to pregnant mothers and 11 aimed to infants [9].
an
However, preventive strategies for bronchiolitis are out of scope of the present review.
M

2. Bronchodilators, corticosteroids and antibiotics

Research-based data, as summarized in numerous meta-analyses and systematic reviews, do not

ed

support the treatment of infant bronchiolitis with bronchodilators like albuterol or epinephrine [10],
the use of anticholinergics [11], or the use of inhaled or systematic corticosteroids [12], or the use
pt

of antibacterial or antiviral agents [13]. Macrolides have some anti-inflammatory influence, may
decrease growth of pathogenic bacteria in respiratory tract, and may even decrease the risk of
ce

subsequent wheezing [14, 15], but do not influence the clinical course of bronchiolitis in infancy
[13]. Seven studies and 824 infants with bronchiolitis treated with antibiotics versus placebo were
Ac

included in the meta-analysis, and there were no significant differences in the length of stay in
hospital, in the duration of oxygen requirement or in readmission rates [13]. Two studies with 281
participants compared azithromycin with placebo and the results in the azithromycin group were
similar to the whole study group [13].

Rarely, Bordetella pertussis and Chlamydia trachomatis may cause infections that clinically
resemble bronchiolitis. These infections need a microbe-specific diagnosis and treatment with
macrolides. In a large multi-center study from USA, B. pertussis was diagnosed by polymerase
chain reaction (PCR) in only 4(0.2%) of 2207 children hospitalized with bronchiolitis during three
winter seasons [16]. In Finland, only one case of B. pertussis and one case of C. trachomatis
infection was found when 228 infants hospitalized for lower respiratory infection at less than 6
months of age were prospectively studied with PCR [17].

2.1. Racemic epinephrine

In an eight-center study from Norway published in 2013, 404 previously healthy infants

t
hospitalized for bronchiolitis at less than 12 months of age were randomized to receive inhaled

ip
racemic epinephrine with a fixed schedule up to every two hours, inhaled racemic epinephrine on-

cr
demand, inhaled 0.9% saline with a fixed schedule up to every two hours, or inhaled 0.9% saline
on-demand [18]. The mean age of the patients was 4.2 months. The primary outcome was the length

us
of stay (LOS) in hospital, and there were no significant differences between the epinephrine and
saline recipients when analyzed separately in the on-demand and fixed-schedule groups, or when
an
analyzed so that these two administration groups were combined.

On-demand inhalation, as compared with fixed-schedule inhalation, was associated with a shorter
LOS in hospital (47.6 vs. 61.3 hours, p=0.01), less use of oxygen supplementation (38.3% vs.
M

48.7%, p=0.04), less need of ventilator support (4.0% vs. 10.8%, p=0.01) and fewer inhalation
treatments (12.0 vs. 17.0, p<0.001) [18]. This result favoring on-demand inhalations is interesting
ed

but difficult to be interpreted. This combined ad hoc analysis has been criticized, since it does not
follow the original randomization into four groups, and both on-demand and fixed-schedule groups
included infants who received racemic epinephrine. Maybe, all maneuvers including also drug and
pt

saline inhalations, which increase the work of breathing, are strenuous for young infants who are at
ce

risk of fatigue and respiratory failure. Simply, infants treated with fixed schedules received more
often potentially harmful inhalations. This highlights the principle of “minimal handling”
minimizing all maneuvers in the treatment of bronchiolitis during the first months of life. An
Ac

alternative explanation is that there was a subgroup of infants who benefitted from on-demand
racemic epinephrine when given well-timed to relieve the worst phases of bronchial obstruction.

Bronchiolitis patients were re-examined at the age of 24 months, and 294(72.8%) children attended
[19]. The follow-up visit consisted of an interview, a clinical examination, and skin prick tests to 17
allergens, determining bronchial obstruction, atopic dermatitis and allergic sensitization. Subgroup
analyses were done in the groups constructed on the basis on these findings. The LOS in hospital
did not differ between patients who received inhaled epinephrine versus 0.9% saline in the
subgroup of 143(48.6%) children who developed recurrent bronchial obstruction by age two years
[19]. Likewise, no significant differences were found in the LOS in hospital in responses to
epinephrine or saline inhalations in 77(26.2%) children with atopic dermatitis or allergic
sensitization by age two [19]. The results do not support the use of inhaled epinephrine in acute
bronchiolitis in infants who are at an increased risk of asthma or allergy.

To summarize the findings from this Norwegian bronchiolitis cohort, inhaled racemic epinephrine
is no more effective than inhaled 0.9% saline in the treatment of bronchiolitis in infants. However,

t
there may be a subgroup of infants with bronchiolitis, who benefit from on-demand inhalations, but

ip
the identification of such a subgroup is not possible in infancy when the patients are in hospital due
to bronchiolitis.

cr
us
2.2. Oral corticosteroids

In a one-center study from Qatar published in 2013, 200 previously healthy children hospitalized
an
for bronchiolitis at less than 18 months of age were randomized to get oral dexamethasone or
placebo on admission and thereafter for four more days [20]. The children were at an increased risk
M
of later asthma, as determined by atopic dermatitis in the child or a family history of asthma in
some first-degree relative. The median age of the recruited patients was 3.5 months, and all received
inhaled albuterol. The mean time to readiness for discharge, which was the primary outcome of the
ed

study, was 18.6 hours in those who received dexamethasone and 27.1 hours in those who received
placebo. Thus, the time to readiness for discharge shortened by 31.3% (p=0.015) in hospitalized
pt

bronchiolitis patients with atopic dermatitis or a family history of asthma. Among secondary
outcomes, 19 dexamethasone and 31 placebo recipients received nebulized epinephrine (p=0.03).
ce

Twenty-two dexamethasone and 19 control patients were re-admitted to the outpatient clinic during
the week after discharge, but none of them needed treatment in hospital [20].
Ac

In a multicenter study from Canada published in 2003, 800 previously healthy children admitted to
the emergency departments of eight hospitals for bronchiolitis at less than 12 months of age were
randomized to get two inhalations of nebulized epinephrine and six doses of oral dexamethasone,
two inhalations of nebulized epinephrine and six doses of oral placebo, two inhalations of placebo
and six doses of oral dexamethasone, or two inhalations of placebo and six doses of oral placebo
[21]. By the seventh day, 17.1% in the epinephrine-dexamethasone group, 23.7% in the epinephrine
group, 25.6% in the dexamethasone group and 26.4% in the placebo group had been admitted to
hospital. In the ad hoc paired comparisons, the epinephrine-dexamethasone group differed
significantly from the placebo group in the non-adjusted analyses (number needed to treat,
NNT=10.8; p=0.02), but did not differ anymore in the adjusted analyses (p=0.07) [21].

To summarize the use of corticosteroids in infants with bronchiolitis, the currently available
guidelines do not recommend the use systemic or inhaled steroid. Although there may be a
subgroup of patients who could benefit from corticosteroids, the effect is slow and demands

t
repeated systemic doses with a potential risk of adverse effects. In addition, the identification of

ip
such a subgroup is not possible during bronchiolitis hospitalization. Thus, there is no need to
change the current recommendation not to give corticosteroids to infants with bronchiolitis.

cr
There were no serious adverse events in these two cited studies on repeated doses of dexamethasone

us
in infants with bronchiolitis, but systematic tests for adrenal insufficiency were not done in either
study. The clinical features of adrenal insufficiency are non-specific and therefore often missed.
an
Accurate biochemical assessment of the pituitary-adrenal axis is the only way to reveal subclinical
insufficiency or even clinical insufficiency with non-specific manifestations [22].
M

3. Hypertonic saline inhalations

ed

3.1. Inpatients

Inhaled nebulized 3% or 5% hypertonic saline (HS) has been actively studied in infant bronchiolitis
pt

during the last 15 years, but no consensus has been reached. Since 2011, Zhang et al. have
ce

published repeated systematic reviews based on meta-analyses [23-26]. The latest systematic review
published in 2017 in the Cochrane Library included 17 randomized controlled trials (RCT) and
1867 infants hospitalized for bronchiolitis at less than 24 months of age [26]. Infants treated with
Ac

nebulized HS had a shorter mean LOS in hospital than those treated with nebulized 0.9% saline
with a mean difference (MD) of -0.41 days and 95% confidence interval (95%CI) of -0.75 to -0.07
(p = 0.02). The 0.41 day difference is less than half of the MD values observed in older Cochrane
reviews [23, 24]. When expressed in hours, the 95%CI of the effect size varied between 1.7 and 18
hours.

To demonstrate the tendencies by time, we undertook a cumulative meta-analysis on the

effectiveness of HS inhalations in bronchiolitis compared to 0.9% saline inhalations or to standard
care without any inhalations [27]. We identified 18 RCT studies including 2102 children treated in
hospital, and the cumulative MD in the LOS in hospital was -0.47 days (95%CI -0.77 to -0.18). The
heterogeneity was substantial between the studies. The cumulative MD reduced by the publication
year, being close to zero in the newest studies. In studies with the upper age limit of 12 months, the
cumulative MD was -0.41 days (95%CI -0.73 to -0.08) without any important heterogeneity. If only
studies with a very low risk of bias were included, the cumulative MD was only -0.03 days and not
anymore significant (95%CI -0.36 to 0.29) [27]. In our earlier meta-analyses, we excluded four
studies from middle-income countries in which the durations of hospitalizations were substantially

t
ip
longer than in western countries [28]. The MD between the HS and 0.9% saline groups was -0.22
days favoring HS treatment. The 95%CI was from -0.54 to 0.10 days, which means that the

cr
difference was not statistically significant [28].

us
There are three clear problems when interpreting the results of the studies on HS inhalations
included in the meta‐analyses. The use of nebulized normal 0.9% saline as a placebo can cause both
beneficial and detrimental effects, and the use of varying bronchodilators is usually not controlled
an
in the original studies and therefore cannot be controlled in the meta-analyses. The use of different
clinical scoring systems leads to varying inclusion criteria in terms of disease severity and to
M
variations in outcome assessments. In addition, the protocols for the inhalation treatments have
varied a lot. The upper age limit of 24 months, instead of 12 months, for the bronchiolitis diagnosis
mean a risk that other than bronchiolitis patients, for example those with reactive airways or even
ed

those with early‐onset asthma, are included.

pt

Only one study published thus far compared inhalations of nebulized HS with standard care without
any drug or saline inhalations [29]. That multi-center study included 10 hospitals and 290 British
ce

infants hospitalized for bronchiolitis at less than 12 months of age. Nebulized 3% HS inhalations
were given six‐hourly until the infant was “fit for discharge”, which was the primary outcome of the
study. There were virtually no differences at all between the nebulized HS inhalation and control
Ac

groups in relation to this primary outcome or in relation to the realized LOS in hospital [29].

To summarize the results on saline inhalations in infants hospitalized for bronchiolitis, nebulized
HS is not useful in the treatment of infants hospitalized for bronchiolitis. The minor impact favoring
the use of HS inhalations in meta-analyses is clinically insignificant, and the cumulative meta-
analyses show that the beneficial effects come from old studies and is approaching the point of no
benefit.
 3.2. Outpatients

A recent meta-analysis included eight RCT studies involving 708 patients treated for bronchiolitis
at less than 24 months of age in the emergency departments or emergency rooms of hospitals [30].
Overall, the meta-analysis showed a 16% reduction in hospitalization rates of patients treated with
nebulized HS compared to 0.9% saline inhalations with a risk ratio (RR) of 0.84 (95%CI 0.71 to
0.98, p=0.03). The corresponding RR was 0.86 (95% CI 0.76 to 0.98) in the 2017 Cochrane review
[26]. However, the heterogeneity between the studies was substantial, and therefore, subgroup

t
analyses were now, in 2018, done to find those patients who may benefit from HS inhalations. In

ip
these additional analyses, the effect was significant only in the group of studies in which HS

cr
inhalations were given together with bronchodilators, more than three doses were administered in
the emergency department, and the risk of bias was low [30].

us
The respective RR was 0.77 (95%CI 0.62 to 0.96) favoring HS inhalations in our cumulative meta-
analysis including eight RCT studies and 1834 bronchiolitis patients [27]. In sensitivity analyses,
an
after removing the large study from USA including 447 patients, the cumulative RR of 0.80 was not
anymore statistically significant (95%CI 0.61 to1.02) [27]. Removing of other studies – one at a
time – did not substantially affect to the results.
M

In the multi-center RCT study from France, 777 infants aged two to 12 months and treated in 24
pediatric emergency departments during two bronchiolitis seasons were randomized to receive
ed

either inhalations of 3% HS or 0.9% normal saline twice 20 minutes apart [31]. By 24 hours, 48.1%
of HS receivers and 52.2% of controls were hospitalized. The adjusted risk difference of -3.2%
pt

favoring HS inhalations was not significant [31]. Mild adverse events such as cough were common
in the HS group, but serious adverse events were not reported in either group.
ce

To summarize the results on saline inhalations in infants treated as outpatients for bronchiolitis,
Ac

inhalations of nebulized HS may reduce the risk of hospitalization in infants treated in the
emergency department, but repeated inhalations are needed. Two inhalations seem not to be
enough. The repetition of inhalations may be difficult in many pediatric emergency rooms or
outpatient clinics without a special pediatric emergency department for delayed stays. Such patients
who need repeated inhalations or other repeated procedures are often, for practical reasons,
transferred to the pediatric ward. Large multicenter studies are warranted to solve whether HS
inhalations are able to reduce hospitalization rates, and the studies should be powered sufficiently
that the infants less than 12 months of age and the patients who do not receive bronchodilators
simultaneously can be analyzed separately.

4. High-flow oxygen therapy

High-flow oxygen therapy (HFOT) through a nasal cannula has been increasingly used in patients
with bronchiolitis, despite the lack of high‐quality research-based evidence on its effectiveness.
Now, two large, prospective, RCT studies published in 2017 [32] and in 2018 [33], showed that

t
ip
using HFOT with a warmed and humidified air‐oxygen mixture is more effective than standard low‐
flow oxygen therapy with non-warmed and non-humidified wall oxygen in infants with

cr
bronchiolitis who need oxygen supplementation.

us
A three‐year RCT study by Kepreotes et al. [32] in one Australian hospital included 202 children
who were admitted for bronchiolitis at less than 24 months of age and needed oxygen
an
supplementation. The flow rate was 1 L/kg/minute (maximum 20 L/minute) in the HFOT group and
a maximum of 2 L/minute in the standard low-flow oxygen group. The main result of the study was
that treatment failures were significantly less common in the HFOT group (14%) than in the
M
standard treatment group (33%, p = 0.002). The treatment failure was defined by the occurrence of
abnormal clinical observations, such as a fall of oxygen saturation to less than 90%, which required
ed

an immediate response by the intensive care team. Furthermore, 61% of the children with treatment
failures in standard therapy were successfully rescued with HFOT. However, HFOT did not shorten
the duration of oxygen support, which was the primary outcome of the study, or did not reduce the
pt

LOS in hospital [32]. These results can be interpreted that an early use of HFOT did not modify the
clinical course of infant bronchiolitis. Instead, the study demonstrated an improvement in a
ce

secondary outcome that is treatment failure, which is very important in clinical practice [32]. The
effect size for this outcome was marked. The mean absolute risk difference in treatment failures
Ac

between the two arms, 19%, corresponds the NNT of 5.3 to prevent one failure. No serious adverse
events occurred in either group. When used as a rescue therapy on the ward, HFOT reduced the
number of patients who required high‐cost intensive care [32].

A three‐year RCT study from Australia and New Zealand by Franklin et al. [33, 34] was carried out
in five tertiary hospitals with PICUs and in 12 regional secondary hospitals with or without PICUs
available. The study comprised 1472 infants who were admitted for bronchiolitis at the age of less
than 12 months and who needed oxygen supplementation. The flow rate was 2 L/kg/minute
(maximum 25 L/minute) in the HFOT group and a maximum of 2 L/minute in the low-flow oxygen
group. The primary outcome was treatment failure, defined by a combination of unfavorable
changes in heart rate, respiratory rate and oxygen fraction of inspired oxygen, which required an
escalation of the HFOT management. The main result of the study was that treatment failures were
significantly less common in the HFOT group (12%) than the standard treatment group (23%,
p < 0.001) [33]. The mean absolute risk difference in treatment failures, 11%, corresponds the NNT
of 9.1 to prevent one failure. Again, 61% of the children with treatment failure in the standard
oxygenation group were successfully rescued with HFOT. HFOT did not shorten the duration of

t
ip
oxygen support or the LOS in hospital. In each group, one case of pneumothorax occurred, thus
affecting less than 1% of the infants [33]. Finally, the admission rate to the PICU was 12% in the

cr
HFOT group and even lower, 9%, in the standard low-flow oxygen group when rescued with HFOT
on the ward if rescue therapy was needed.

us
These two excellent studies documented the superiority of HFOT over low‐flow standard therapy
for oxygen administration in infants with bronchiolitis who needed oxygen supplementation. Two
an
fundamental questions arise from the results. First, should we routinely use HFOT instead of low‐
flow oxygen administration for all bronchiolitis patients who need oxygen supplementation? In the
M
studies by Kepreotes et al. [32] and Franklin et al. [33], two-thirds of the bronchiolitis patients who
needed oxygen supplementation could be treated with standard low‐flow oxygen administration,
and the rescue therapy with HFOT for children who failed with standard oxygen administration
ed

worked well. This practice is pragmatic and is in use in most pediatric hospitals. Second, do we still
need new RCT studies in which infants with bronchiolitis are by random allocated to HFOT or to
pt

standard oxygen administration arms? Indeed, we do not know whether such an approach would
reduce the need of intubations and mechanical ventilations. However, the sample sizes required for
ce

such studies would be very large, and finally, meta-analyses combining data from different studies
may be needed to answer this question. Furthermore, the effectiveness of HFOT may differ in
Ac

children younger than 12 months with RSV bronchiolitis compared to children older than
12 months with rhinovirus‐induced wheezing and asthma‐like obstruction of airways. Thus, RCT
studies on HFOT are still needed, but to give answers to clinically crucial questions, the studies
should be well-powered multi-center studies allowing stratified analyses at least based on age, virus
etiology and previous wheezing history.

Before the introduction of HFOT, nasal CPAP (nCPAP) was in most hospitals the first-line
treatment for those infants who failed to respond appropriately to the traditional low-flow oxygen
supplementation [35]. However, there are no prospective RCT studies comparing HFOT and
nCPAP in infants with bronchiolitis thus far available, and the results of retrospective chart reviews
are conflicting [35]. It can be expected that nCPAP is more effective than HFOT, but in most
children`s hospitals, treatment with nCPAP takes place in the PICU, opposite to HFOT which can
be carried out on the pediatric ward. In addition, nCPAP is more invasive than HFOT requiring a
tight nasal tube. Obviously, the expensive intensive care can be avoided when HFOT is actively
used for infants with bronchiolitis on the wards [32, 33, 36]. A recent prospective, randomized,
open-label pilot study made in the PICU of a tertiary-care hospital compared HFOT and nCPAP in

t
ip
31 Indian infants with bronchiolitis who needed oxygen supplementation at age less than six
months [37]. One patient in each group had to be intubated, but HFOT was considered to be better,

cr
compared to nCPAP, tolerated by the patients and better accepted by the nurses and parents [37].

us
To summarize the results on oxygen administration in infants hospitalized for bronchiolitis who
need oxygen supplementation, management with HFOT is superior to low-flow oxygen
administration, but research-based data are lacking on the clinical indications of HFOT treatment,
an
on the appropriate flows and oxygen fractions of inspired air, and in particular, on the optimal
protocols for weaning off the HFOT therapy. In Finnish hospitals, an important problem was just
M
the lack of protocols how to stop HFOT to avoid unnecessarily slow weaning times and long
durations of oxygen supplementation leading to long stays in hospital [36]. Prospective, large
studies are needed to solve who of the infants with bronchiolitis can be treated with traditional low-
ed

flow oxygenation, who of them will benefit from HFOT and who of them must be treated with
nCPAP or even with mechanical ventilation as intubated.
pt
ce

5. Use of medicines in clinical practice

Most current evidence-based guidelines on the management of bronchiolitis in infants settle the
Ac

upper age limit to 24 months and recommend that any inhaled or systemic drugs should not be
routinely used, as summarized recently [2]. However, the use of different drugs is common and
there is marked variation between countries [38] and even between the hospitals of the same
country [39]. Twenty-nine percent of 3725 infants treated at less than 12 months of age in the
emergency departments of 38 hospitals in Canada, United States, Australia and New Zealand,
United Kindom and Ireland, or Spain and Portugal, received epinephrine (mean 11%, range 0.4-
25%), albuterol (14%, 3-29%), hypertonic saline (7.5%, 0.7-24%), or corticosteroids (2.3%, 1.4-
4%) [38].
The most recent study from USA included 17 hospitals and 1,016 infants admitted for bronchiolitis
at less than 12 months of age [40]. Half of them received at least one albuterol inhalation before
admission. In adjusted analyses, the risk factors for albuterol treatments were prior use of
bronchodilators with adjusted odds ratio (aOR) of 1.89 (95%CI 1.24-2.90) and presence of
wheezing before the current episode (aOR 3.94, 95%CI 2.61-2.90) [40]. This means that these
children had repeated wheezing, not bronchiolitis that should be the first wheezing episode during a
lower respiratory infection. The use of albuterol may be justified in infants with repeated wheezing
which probably means the presence of reactive airways and sometimes even early-onset asthma.

t
ip
As expected, the use of drug therapies is more common in the PICUs than on the wards or in the

cr
outpatient settings. In a Finnish one-center 16-year study, the use of inhaled beta-agonists in 105
infants, who were treated for bronchiolitis in the PICU, decreased from 68% to 38% and that of

us
systemic corticosteroids from 29% to 5%, but the use of racemic epinephrine increased from 59% to
85% during a surveillance period from 2000 to 2015 [41]. Currently, the effectiveness of inhalations
an
with racemic epinephrine is questioned, and such inhalations are not recommend for routine use
[18]. The use of antibiotics remained rather stable, varying between 34% and 43% [41]. A recent
Canadian study evaluated the practices of 57 intensive care doctors who attended the treatment of
M

bronchiolitis patients, and 59% of recipients answered of prescribing racemic epinephrine and 36%
inhaled albuterol for bronchiolitis cases treated in the PICU [42]. Two-thirds (71%) prescribed
ed

antibiotics to those bronchiolitis patients who were mechanically ventilated [42].

To summarize the data on medications in infants with bronchiolitis, the prescription of medicines
pt

has varied substantially between different countries, and even between different hospitals of the
ce

same country. Medications including antibiotics are used more in the PICUs than on the wards, in
the emergency departments or in the emergency rooms. The severity of the disease influences to the
prescriptions of medicines, including those medicines without any research-based evidence on their
Ac

effectiveness in bronchiolitis. Currently available bronchiolitis guidelines are based on both

ambulatory and hospital studies performed in infants with mild-to-moderate bronchiolitis.
Therefore, future guidelines for infants with bronchiolitis should separately address severe cases
and, in particular, cases requiring intensive care for severe bronchiolitis. In addition, bronchiolitis
and repeated wheezing are different clinical entities, which should be taken into account in the
guidelines. If the same bronchiolitis guidelines are applied for the groups with and without repeated
wheezing, there is a risk of under-treatment of children with repeated wheezing. Some of them have
even an early-onset asthma. On the other hand, infants with true bronchiolitis, that is the first
episode of respiratory distress during lower respiratory infection without any wheezing history, are
in many hospitals exposed to unnecessary drug therapies.

6. “Minimal handling” – back to basics

The concept of “minimal handling” was re-launched for treatment of infants with bronchiolitis in
the SABRE study, which evaluated 317 infants hospitalized for bronchiolitis at less than 12 months
of age [29]. Half of the cases were randomized to receive HS inhalations without bronchodilators

t
every six hour and half, the controls, received standard supportive care without any saline or drug

ip
inhalations. Standard care involved oxygen administration if needed, fluid administration as

cr
appropriate to the severity of the disease, and “minimal handling” [29]. The practice of “minimal
handling” means avoiding of all unnecessary invasive maneuvers, such as taking repeated blood

us
samples, monitoring with invasive methods, giving routine inhalations, performing routine
suctioning or doing any other disturbing procedures for sick infants.
an
Monitoring of fluid intake, oxygen saturation and the work of breathing, and fluid and oxygen
supplementation if needed and respiratory support if necessary, are still the cornerstones of the
treatment of infants with bronchiolitis. Fluids can be given either intravenously or via nasogastric
M

tubes. Nasogastric tubes allow better nutrition but may increase nasal mucus secretion leading to
nasal obstruction. There is no research-based evidence which of the practices is better. If
ed

respiratory support is needed due to decreased oxygen saturation or increased breathing work,
HFOT is an alternative that is less invasive than nCPAP or ventilation as intubated. In addition,
HFOT can be carried out on a well-supplied pediatric ward without any need to transfer the patient
pt

to an intensive care unit.

ce

7. Conclusion
Ac

Numerous studies, as summarized in meta-analyses and systematic reviews, have proved the
ineffectiveness of beta-agonists, anticholinergics, antibiotics, and inhaled corticosteroids in infants
with bronchiolitis. However, age limits and clinical definitions of bronchiolitis differ substantially
between different studies, which makes the comparisons of the results and their appropriate
incorporations in the meta-analyses difficult. An RCT study from Norway suggested that there
probably are some bronchiolitis patients, who may benefit from well-timed, on-demand inhalations
of racemic epinephrine. In two RCT studies from Qatar and USA, the effect of systemic
corticosteroids was marginal and repeated doses were needed, which means a risk of adrenal
suppression. Based on recent meta-analyses, inhalations of hypertonic saline do not shorten the
LOS in hospital, but such inhalations may decrease the hospitalization rates when given more than
three times in the emergency department. In two large, prospective, well-designed RCT studies
from Australia and New Zealand, HFOT with warmed and humidified air-oxygen mixture was more
effective than the standard low-flow oxygenation in infants with bronchiolitis. However, HFOT did
not shorten the duration of oxygen supplementation or the LOS in hospital. In addition, two-thirds
of infants, who were hospitalized for bronchiolitis and who needed oxygen supplementation, could

t
ip
be treated with standard low-flow oxygen administration, and over half of those who failed with
standard oxygen therapy could be rescued with HFOT on the pediatric ward. Currently, HFOT is

cr
the only new and promising approach for the treatment of infants with bronchiolitis.

8. Expert commentary

us
an
We know well which therapies are not effective in the routine treatment of infants with
M
bronchiolitis: bronchodilators like albuterol or epinephrine, anticholinergics, antibacterial or
antiviral medicines, and inhaled or systematic steroids. However, we do not know how infants with
bronchiolitis should be treated, and therefore, clinicians try out different treatments with “an idea to
ed

do something what might help”. Any substantial steps forward are not expected, at least in near
future, in the field of pharmaceutical therapy of infants with bronchiolitis. Drugs that are useful in
pt

children with bronchial obstruction do not help in infants younger than 12 months with
bronchiolitis. Therefore, completely new and different pharmaceutical approaches would be needed,
ce

but such options are not on the horizon.

Likewise, inhalations of normal or hypertonic saline are not useful. A great number of studies have
Ac

been done on hypertonic saline inhalations, and the benefits over normal saline inhalations in
hospitalized patients have been marginal. The use of hypertonic saline inhalations in emergency
departments has decreased the need for hospitalization, but the effect of the treatment has been
minor and repeated inhalations have been required, which is not realistic in many hospitals.

High-flow oxygen therapy (HFOT) is a new approach to the supportive care of infants with
bronchiolitis who need oxygen supplementation and relief of respiratory work. Two recent excellent
studies proved the superiority of HFOT with warmed and moistened air-oxygen mixture over the
traditional low-flow oxygen therapy. However, we do not know whether HFOT is capable to
modify the course of bronchiolitis, or whether it only means a supportive care for bronchiolitis
patients who need oxygen supplementation.

Interestingly, a pragmatic approach to treat infants with bronchiolitis, who need supplementary
oxygen, first with traditional low-flow wall oxygen and then with HFOT only if the low-flow
therapy fails, was even a little bit more effective than the approach to start HFOT routinely for all
infants who need oxygen administration. There are two pitfalls concerning especially the weaning
of bronchiolitis patients from HFOT therapy. The flow rate during HFOT should not decrease to

t
less than 0.5 ml/kg/minute, since the use of such flow means low-flow therapy, which may even be

ip
harmful when given through the tight HFOT cannula. The volume of oxygen-air mixture may be
too small for an effective inspiration. In addition, slow weaning leads to unnecessarily long HFOT

cr
treatments and finally to longer stays on the ward and in the hospital. Thus, the indications of

us
HFOT in infant bronchiolitis, the starting protocols, and especially the weaning protocols need
further development. an
The cornerstones of bronchiolitis therapy have been – and are still – monitoring of oxygen
saturation and fluid intake, and oxygen supplementation and fluid administration if needed. An old
but in many hospitals forgotten treatment principle is “minimal handling”, which means avoiding of
M
all unnecessary invasive maneuvers, such as taking repeated blood samples, monitoring with
invasive methods, giving routine inhalations, performing routine suctioning or other physical
ed

procedures, or doing any other disturbing procedures for sick infants. The necessary treatments
should be given as gently as possible.
pt

The work of breathing needs clinical monitoring in hospitalized infants with bronchiolitis, which
means regular assessments of respiratory rate, chest retractions and the mental and motoric activity
ce

of the infant. Well-timed starting of HFOT not only improves oxygenation but also seems to reduce
the work of breathing. Finally, the rescue with HFOT reduces the need of more invasive treatments,
such as nCPAP or mechanical ventilation as intubated, and the admission rates to the PICUs.
Ac

9. Five-year view

Probably, the researchers will not do any marked innovations in the field of pharmaceutical therapy
of infants with bronchiolitis within the next five years. The development of vaccines against RSV is
just now very active but prevention of bronchiolitis is out of scope of this review.
The studies in near future will probably prove that inhalations of hypertonic saline are not useful in
bronchiolitis, independently of whether the treatment is offered on the hospital ward or in the
emergency department or emergency room.

Within some years, high-flow oxygen therapy (HFOT) will reach the status of an established
treatment in infant bronchiolitis. However, there is a need to develop the protocols for starting of
HFOT and more importantly, for weaning from HFOT. However, all infants with bronchiolitis who
need oxygen supplementation cannot and need not to be treated with HFOT. Therefore, it is

t
important to find the balance between the use of high-flow and low-flow therapies, that is when to

ip
use HFOT with warmed and moistened air-oxygen mixture and when with the traditional low-flow
therapy with wall oxygen.

cr
us
Key issues

• The variation in the definition of bronchiolitis makes difficult to compare the results of
an
different studies and causes substantial heterogeneity to the meta-analyses.

• An important issue is the upper age limit applied in the definition of infant bronchiolitis, 12
M

months or 24 months. In future, the analyses should be done separately for infants aged less
and more than 12 months
ed

• Bronchodilators are not effective in bronchiolitis, but inhaled racemic epinephrine given on-
demand for severe bronchiolitis may diminish bronchial obstruction, if present, in some
pt

patients.

• Inhaled or systemic corticosteroids are not useful in bronchiolitis, but systemic

ce

dexamethasone, when given in addition to bronchodilators for five to six days, diminished
obstructive symptoms. However, repeated doses increase the risk of adrenal suppression,
Ac

and therefore cannot belong to the routine treatment of infants with bronchiolitis.

• There are no means to identify those bronchiolitis patients, who might benefit from
inhalations of racemic epinephrine or from systemic steroids.

• Inhalations of 3-5% hypertonic saline are not useful in infants hospitalized for bronchiolitis,
as documented by recent studies and the cumulative meta-analysis.
 • Inhalations of 3-5% hypertonic saline may decrease the rates of hospitalizations, but
repeated inhalations are needed in the emergency departments, which is not realistic in many
pediatric outpatient clinics.

• High-flow oxygen therapy (HFOT) with warmed and moistened oxygen-air mixture is
superior to traditional low-flow oxygen therapy. In two large RCT studies, more than 60%
of infants hospitalized for bronchiolitis who needed oxygen supplementation, could be
treated with low-flow therapy, and 60% of failures could be rescued with HFOT.

t
ip
• The researchers need to develop the starting, maintaining and weaning-off protocols for
HFOT, to avoid too low or high flows during HFOT and too long treatment times.

cr
• The cornerstones of bronchiolitis therapy are still oxygen administration if needed, fluid
administration as appropriate to the severity of the disease, and “minimal handling” that

us
means avoiding of all unnecessary maneuvers and carrying out the necessary treatments as
gently as possible.
an
Funding
M

This paper was not funded.

ed

Declaration of interest
pt

The author has no relevant affiliations or financial involvement with any organization or entity with
a financial interest in or financial conflict with the subject matter or materials discussed in the
ce

manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert
testimony, grants or patents received or pending, or royalties.
Ac

Reviewers Disclosure

Peer reviewers on this manuscript have no relevant financial relationships or

otherwise to disclose.
References
Papers of special note have been highlighted as:

* of interest

** of considerable interest

1. Smyth RL, Openshaw PJ. Bronchiolitis. Lancet. 2006; 368: 312-22

t
2. Florin TA, Plint AC, Zorc JJ. Viral bronchiolitis. Lancet. 2017; 389: 211-24

ip
cr
3. Pruikkonen H, Uhari M, Dunder T, et al. Infants under 6 months with bronchiolitis are most
likely to need major medical interventions in the 5 days after onset. Acta Paediatr. 2014; 103:

us
1089-93
an
4. Jartti T, Aakula M, Mansbach JM, et al. Hospital length-of-stay is associated with rhinovirus
etiology of bronchiolitis. Pediatr Infect Dis J. 2014; 33: 829-34
M

5. Ralston S, Hill V. Incidence of apnea in infants hospitalized with respiratory syncytial virus
bronchiolitis: a systematic review. J Pediatr. 2009; 155: 728-33.
ed

6. Jartti T, Korppi M. Rhinovirus-induced bronchiolitis and asthma development. Pediatr

Allergy Immunol. 2011; 22: 350-5
pt

7. Megalaa R, Perez GF, Kilaikode-Cheruveettara S, et al. Clinical definition of respiratory

ce

viral infections in young children and potential bronchiolitis misclassification. J Investig

Med. 2018; 66: 46-51
Ac

8. Korppi M, Koponen P, Nuolivirta K. Upper age limit for bronchiolitis: 12 months or 6

months? Eur Respir J. 2012; 39: 787-8

9. Mazur NI, Higgins D, Nunes MC, et al. Respiratory Syncytial Virus Network (ReSViNET)
Foundation. The respiratory syncytial virus vaccine landscape: lessons from the graveyard
and promising candidates. Lancet Infect Dis. 2018: 18: e295-e311
10. Gadomski AM, Scribani MB. Bronchodilators for bronchiolitis. Cochrane Database Syst
Rev. 2014; 6: CD001266

11. Everard ML, Bara A, Kurian M, et al. Anticholinergic drugs for wheeze in children under
the age of two years. Cochrane Database Syst Rev. 2005; 3: CD001279

12. Fernandes RM, Bialy LM, Vandermeer B, et al. Glucocorticoids for acute viral bronchiolitis

t
in infants and young children. Cochrane Database Syst Rev. 2013; 6: CD004878

ip
cr
13. Farley R, Spurling GK, Eriksson L, et al. Antibiotics for bronchiolitis in children under two
years of age. Cochrane Database Syst Rev. 2014; 10: CD005189

us
14. Beigelman A, Isaacson-Schmid M, Sajol G, et al. Randomized trial to evaluate
an
azithromycin's effects on serum and upper airway IL-8 levels and recurrent wheezing in
infants with respiratory syncytial virus bronchiolitis. J Allergy Clin Immunol. 2015; 135:
M
1171-8
ed

15. Zhou Y, Bacharier LB, Isaacson-Schmid M, et al. Azithromycin therapy during respiratory
syncytial virus bronchiolitis: Upper airway microbiome alterations and subsequent recurrent
wheeze. J Allergy Clin Immunol. 2016; 138: 1215-9
pt
ce

16. Piedra PA, Mansbach JM, Jewell AM, et al. Bordetella pertussis is an uncommon pathogen
in children hospitalized with bronchiolitis during the winter season. Pediatr Infect Dis J.
2015; 34: 566-70.
Ac

17. Honkila M, Kallinen V, Renko M, et al. Chlamydia trachomatis, Bordetella pertussis and
other respiratory bacteria in the aetiology of lower respiratory tract infections in young
infants. Acta Paediatr. 2018 (in press)

18. Skjerven HO, Hunderi JO, Brügmann-Pieper SK, et al. Racemic adrenaline and inhalation
strategies in acute bronchiolitis. N Engl J Med. 2013; 368: 2286-93
19. Skjerven HO, Rolfsjord LB, Berents TL, et al. Allergic diseases and the effect of inhaled
epinephrine in children with acute bronchiolitis: follow-up from the randomised, controlled,
double-blind trial. Lancet Respir Med. 2015; 3: 702-8

20. Alansari K, Sakran M, Davidson BL, et al. Oral dexamethasone for bronchiolitis: a
randomized trial. Pediatrics. 2013; 132: e810-6

t
ip
21. Plint AC, Johnson DW, Patel H, et al. Epinephrine and dexamethasone in children with

cr
bronchiolitis. N Engl J Med. 2009; 360: 2079-89

us
22. Zöllner EW. Hypothalamic-pituitary-adrenal axis suppression in asthmatic children on
inhaled corticosteroids: Which test should be used? Pediatr Allergy Immunol. 2007; 18: 401-
an
9
M

23. Zhang L, Mendoza-Sassi RA, Wainwright C, et al. Nebulized hypertonic saline solution for
acute bronchiolitis in infants. Cochrane Database Syst Rev. 2008; 4: CD006458
ed

24. Zhang L, Mendoza-Sassi RA, Wainwright C, et al. Cochrane Database Syst Rev. 2013; 7:
CD006458
pt

25. Zhang L. Hypertonic saline for bronchiolitis - a meta-analysis reanalysis. J Pediatr. 2016;
ce

176: 221-4

26. Zhang L, Mendoza-Sassi RA, Wainwright C, et al. Nebulised hypertonic saline solution for
Ac

acute bronchiolitis in infants. Cochrane Database Syst Rev. 2017; 12: CD006458

27. Heikkilä P, Renko M, Korppi M. Hypertonic saline inhalations in bronchiolitis - A

cumulative meta-analysis. Pediatr Pulmonol. 2018; 53: 233-42
* Cumulative meta-analysis including 22 studies from 2004 to 2016 shows that the
effectiveness of inhalations of hypertonic saline measured as odds ratios is approaching the
no-effect point compared to inhalations of normal saline or to no inhalations in infants with
 bronchiolitis. The effectiveness of hypertonic saline that is still seen in meta-analyses comes
from old studies with more heterogeneity and less quality than the new studies.

28. Heikkilä P, Korppi M. Nebulised hypertonic saline inhalations do not shorten hospital stays
in infants with bronchiolitis. Acta Paediatr. 2016; 105: 1036-8.

29. Everard ML, Hind D, Ugonna K, et al. SABRE: a multicentre randomised controlled trial of
nebulised hypertonic saline in infants hospitalised with acute bronchiolitis. Thorax. 2014; 69:

t
ip
1105-12
** The only prospective randomized controlled study including 12 hospitals on inhalations of

cr
hypertonic saline compared to “minimal handling” without any inhalations in 290 less than
six months old infants with bronchiolitis. The study groups did not differ in terms of length

us
of stay in hospital or duration of oxygen administration. The study re-launched an old
concept of “minimal handling” in the treatment of young infants with severe bronchiolitis.
an
30. Zhang L, Gunther CB, Franco OS, et al. Impact of hypertonic saline on hospitalization rate
in infants with acute bronchiolitis: A meta-analysis. Pediatr Pulmonol. 2018; 53: 1089-95
M

31. Angoulvant F, Bellêttre X, Milcent K, et al. Effect of nebulized hypertonic saline treatment
ed

in emergency departments on the hospitalization rate for acute bronchiolitis: A randomized

clinical trial. JAMA Pediatr; 171: e171333
pt

32. Kepreotes E, Whitehead B, Attia J, et al. High-flow warm humidified oxygen versus
ce

standard low-flow nasal cannula oxygen for moderate bronchiolitis: an open, phase 4,
randomised controlled trial. Lancet. 2017; 389: 930-9.
** The first prospective randomized controlled trial on high-flow oxygen therapy (HFOT)
Ac

with humidified and warmed air-oxygen mixture in bronchiolitis. When treatment failure was
the outcome measure, HFOT was significantly more effective than traditional low-flow
oxygenation in this one-hospital study including 202 children hospitalized for bronchiolitis at
less than 24 months of age. Sixty-one percent of those who failed with low-flow therapy
were successfully rescued with HFOT on the ward without any need of admitting the patient
to an intensive care unit.
33. Franklin D, Babl FE, Schlapbach LJ, et al. A randomized trial of high-flow oxygen therapy
in infants with bronchiolitis. N Engl J Med. 2018; 378: 1121-31.
** The second prospective randomized controlled trial on high-flow oxygen therapy (HFOT)
with humidified and warmed air-oxygen mixture in bronchiiolitis. When treatment failure
was the outcome measure, HFOT was significantly more effective than traditional low-flow
oxygenation in this multi-center study including 12 hospitals and 1472 children. Sixty-one
percent of those who failed with low-flow therapy were successfully rescued with HFOT on
the ward without any need of admitting the patient to an intensive care unit.

t
ip
34. Franklin D, Dalziel S, Schlapbach LJ, et al. Early high flow nasal cannula therapy in

cr
bronchiolitis, a prospective randomised control trial (protocol): A paediatric acute respiratory
intervention study (PARIS). BMC Pediatr. 2015; 15: 183.

us
35. Sinha IP, McBride AKS, Smith R, et al. CPAP and high-flow nasal cannula oxygen in
an
bronchiolitis. Chest. 2015; 148: 810-23

36. Sokuri P, Heikkilä P, Korppi M. National high-flow nasal cannula and bronchiolitis survey
M

highlights need for further research and evidence-based guidelines. Acta Paediatr. 2017; 106:
1998-2003
ed

37. Sarkar M, Sinha R, Roychowdhoury S, et al. Comparative Study between noninvasive

continuous positive airway pressure and hot humidified high-flow nasal cannulae as a mode
pt

of respiratory support in infants with acute bronchiolitis in pediatric intensive care unit of a
ce

tertiary care hospital. Indian J Crit Care Med. 2018; 22: 85-90

38. Schuh S, Babl FE, Dalziel SR, et al. Practice variation in acute bronchiolitis: A pediatric
Ac

emergency research networks study. Pediatrics. 2017; 140: e20170842

39. Elenius V, Bergroth E, Koponen P, et al. Marked variability observed in inpatient

management of bronchiolitis in three Finnish hospitals. Acta Paediatr. 2017; 106: 1512-8

40. Condella A, Mansbach JM, Hasegawa K, et al. Multicenter study of albuterol use among
infants hospitalized with bronchiolitis. West J Emerg Med. 2018; 19: 475-83.
41. Mecklin M, Heikkilä P, Korppi M. The change in management of bronchiolitis in the
intensive care unit between 2000 and 2015. Eur J Pediatr. 2018; 177: 1131-7

42. Bradshaw ML, Déragon A, Puligandla P, et al.. Treatment of severe bronchiolitis: A survey
of Canadian pediatric intensivists. Pediatr Pulmonol. 2018; 53: 613-8

t
ip
cr
us
an
M
ed
pt
ce
Ac