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Transcript of Bronchiolitis[2011]
C
Update on management of bron
chiolitisSuzanne Schuha,b,caResearch Institute, The Hospital for Sick Children,bDivision of Paediatric Emergency Medicine andcDepartment of Paediatrics, University of Toronto,Toronto, Ontario, Canada
Correspondence to Suzanne Schuh, The Hospital forSick Children, 555 University Ave., Toronto, ON M5G1X8, CanadaTel: +1 416 813 6239; fax: +1 416 813 5043;e-mail: [email protected]
Current Opinion in Pediatrics 2011, 23:110–114
Purpose of review
Bronchiolitis impacts millions of infants worldwide. Although several therapeutic options
stem from highly plausible theoretical rationales for success and some may even offer
modest short-term symptom relief, none has been conclusively shown to alter the
course of the disease or its major outcomes. However, several recent papers shed light
on which treatments show promising preliminary evidence and offer insight into future
research endeavors on this topic. This review will summarize bronchiolitis therapy in
view of this recent evidence.
Recent findings
The agents in which theory promises but treatment does not deliver include systemic
corticosteroids alone, inhaled bronchodilators alone and antileukotrienes. The most
promising combination to date appears to be that of oral dexamethasone and inhaled
epinephrine but numerous related issues need to be clarified further. Caretakers need to
be counselled about the usual protracted clinical course of bronchiolitis.
Summary
Because bronchiolitis is a highly heterogeneous entity, future research challenges
should include detailed characterization of infants most likely to benefit from given
interventions. In the meantime, stick with the good old time-honored supportive route!
Keywords
bronchiolitis, dexamethasone, epinephrine, heliox, respiratory distress
Curr Opin Pediatr 23:110–114� 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins1040-8703
IntroductionBronchiolitis is the leading cause of infant hospitaliz-
ations during the first year of life [1]. It is usually defined
as the first viral episode of respiratory distress, accom-
panied by coryza, cough, crepitations and wheezing [2].
The respiratory syncytial virus (RSV) accounts for the
majority of cases [3], although other important viruses
have also been implicated [4–6]. Several excellent
reviews of the etiology and treatment approaches to
bronchiolitis have recently been published [7–11], all
of which highlight importance of oxygenation, hydration
and airway support if necessary [12,13].
However, no single pharmacological agent has been
conclusively found to change the course of the disease.
An important challenge is that bronchiolitis has wide
etiologic heterogeneity, encompassing the only episode
of viral-induced wheezing and the first attack of episodic
wheezing without atopy/interval symptoms as well as the
initial exacerbation of a multitrigger wheeze often associ-
ated with asthma [7]. The bad news is that these wheez-
ing phenotypes respond differently to treatment [7].
Because it is impossible to reliably identify these sub-
groups during their initial presentation, interpretation of
opyright © Lippincott Williams & Wilkins. Unautho
1040-8703 � 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins
the results of therapeutic trials of bronchiolitis becomes
challenging [14,15].
In 2006, the American Academy of Pediatrics (AAP)
released a comprehensive evidence-based guideline on
the management of bronchiolitis [16]. Since then, two
large multicenter bronchiolitis trials have shed light on
the management with oral dexamethasone with and
without nebulized epinephrine [17��,18] and raised sev-
eral unanswered questions. Furthermore, several recent
systematic reviews of various other inhaled therapies
guide us when these interventions may be effective
[19–21]. Two recent bronchiolitis papers have clarified
predictors of the return for care after discharge from the
emergency department (ED) [22�] and highlighted the
usual protracted course of this disease [9]. This review
will therefore focus on the update of pharmacotherapy in
bronchiolitis in light of this recent information.
Supplemental oxygenSince the invention of routine transcutaneous oxygen
saturation monitoring two decades ago, the hospitaliz-
ation rate for bronchiolitis has increased 2.5-fold, without
increase in mortality [23]. Several authors postulate the
rized reproduction of this article is prohibited.
DOI:10.1097/MOP.0b013e3283425442
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Management of bronchiolitis Schuh 111
Key points
� Systemic corticosteroids alone, inhaled bronchodi-
lators alone and anti-leukotrienes do not change the
clinical course and outcomes in bronchiolitis.
� The most promising therapeutic combination to
date may be that of oral dexamethasone and inhaled
epinephrine but many issues need to be clarified
further.
� Caretakers need to be counselled about the usual
protracted clinical course of bronchiolitis.
� Future research should focus on characterization of
infants most likely to benefit from given interven-
tions.
use of oximetry is at least in part related to this increase in
admissions [24]. The significance of mild hypoxemia with
saturations below 95% as it relates to bronchiolitis out-
comes has not been specifically studied and the
thresholds for administering supplemental oxygen vary
widely [25–29]. Indeed, a small difference in oximetry of
minimal physiologic significance between 94 and 92% has
been shown on its own to raise postulated hospitalization
rate from 58 to 85% [24]. Another study showed that
approximately 26% of infants with bronchiolitis experi-
ence prolonged hospital stays based on periodic desatura-
tions, despite satisfactory clinical status [30,31]. As a
result of the arbitrary nature of various thresholds for
using supplemental oxygen which are likely not cost-
effective [31–33], the AAP recommends the use of this
intervention in previously healthy infants with satur-
ations below 90% [16]. Further studies of the impact
of desaturations and mild hypoxemia on bronchiolitis
outcomes are needed.
BronchodilatorsBoth nebulized epinephrine and albuterol are commonly
given for bronchiolitis, with highly variable frequency
[34]. The attractive features of inhaled epinephrine in
bronchiolitis include its vasoconstrictive and beta agonist
properties [35,36]. Because patients with bronchiolitis are
a highly heterogeneous group, some of whom may have
their first asthma episode, the AAP guideline recom-
mends that a monitored trial of a bronchodilator may
be given [16]. However, this guideline strongly advises
against routine use of bronchodilators in this disease and
recent evidence outlined below certainly points to
this conclusion.
Of the four studies published since 2003 focusing on short-
term outcomes after nebulized epinephrine versus albu-
terol/placebo in bronchiolitis [37–40], the largest was a
multicenter randomized controlled trial from 2008 which
found no difference between three consecutive doses of
nebulized albuterol and a single dose of epinephrine [40].
Likewise, hospitalized infants given nebulized epineph-
rine appear to derive no added benefit compared with
those treated with albuterol or placebo [33,41]. A systema-
tic review [20] showed four of five inpatient studies
demonstrated no benefit of epinephrine over placebo with
respect to the clinical score [20]. Although the authors
found some evidence of short-term clinical benefit of
epinephrine over albuterol in the four included outpatient
studies, epinephrine inferred no advantage with respect to
hospitalization. They recommend a large randomized
controlled trial comparing epinephrine with placebo and
salbutamol in the outpatient setting.
A recent Canada-wide trial compared the impact of two
doses of nebulized epinephrine, daily oral dexametha-
opyright © Lippincott Williams & Wilkins. Unauth
sone and the combination of both with the use of two
placebos in 800 previously healthy outpatients with
bronchiolitis in the ED [17��]. Although infants in the
epinephrine group had achieved significantly lower
clinical scores during the initial hour of the study com-
pared with those receiving placebo, there was no impact
of epinephrine on hospitalization and this intervention
was accompanied by more side-effects.
CorticosteroidsA recent systematic review of 13 trials of 1198 children
with bronchiolitis given systemic corticosteroids showed
no difference in hospitalization, length of hospital stay,
clinical scores and readmission rates compared with
placebo [42]. The AAP guideline also recommends
against the use of corticosteroids in bronchiolitis [16].
Since then, two large multicenter placebo-controlled
trials have been carried out [17��,18]. The first was a
US trial which found that a single high dose of oral
dexamethasone conveys no benefit compared with
placebo with respect to hospitalizations from the ED,
length of stay, return for care or clinical score [18]. Shortly
thereafter, the aforementioned Canada-wide study by
Plint et al. [17��] used a factorial design to compare the
effect of daily dexamethasone alone, two doses of inhaled
epinephrine in the ED alone and the combination of the
two with using two placebos. Although neither agent
alone produced any benefit, the authors found that the
dexamethasone–epinephrine combination resulted in a
nine-percentage point reduction in hospitalization within
7 days [17��]. The authors postulated this potential
beneficial effect may stem from a synergy between the
two therapeutic agents. Although this difference may
translate into substantial reduction in hospitalizations
in the population as a whole, this effect size is relatively
modest. Because the effects of the high dose of dexa-
methasone used on the brain and lungs of babies are
uncertain [43], this treatment cannot be currently recom-
mended without further evidence. For these reasons, it
orized reproduction of this article is prohibited.
C
112 Infectious diseases and immunization
seems prudent to investigate a corticosteroid dose con-
siderably smaller compared with that used in the study by
Plint. The optimal treatment duration is also unknown,
and, although a previous small study showed infants
given regular albuterol with a single dose of oral dexa-
methasone achieved outcomes comparable to those given
a longer course of corticosteroids, this needs to be verified
in a large trial [44].
A recent small but worthwhile study clarifies the reasons
for the lack of benefit of isolated steroid therapy in
bronchiolitis [45]. The authors showed that dexametha-
sone fails to produce anti-inflammatory effect in acute
RSV bronchiolitis because it lacks sufficient impact on
the production of inflammatory cytokines which play a
major role in this disease.
Hypertonic salineBoth the hypertonic saline and deoxyribonuclease agents
work by decreasing viscosity of airway mucus [46–
48,49�]. A recently published Cochrane Systematic Reviewof four trials [46,50–52] involving 254 infants with acute
bronchiolitis found that 3% saline results in a significantly
shorter length of hospital stay as well as a lower clinical
score [19]. However, none of these studies involved
infants presenting to the ED. A recent small ED study
of this population using inhaled hypertonic saline and
epinephrine versus normal saline and epinephrine found
no difference between these interventions with respect
to the improvement in the clinical score, oxygen satur-
ation, hospitalization and return for care [53�]. Likewise,
two inpatient studies of the deoxyribonuclease have
demonstrated no benefit [47,48]. Clearly, not enough
compelling evidence currently exists to recommend
the use of mucolytic agents in bronchiolitis and further
research is necessary.
A recent published review article clarifies the postulated
basic science mechanisms of action involving hypertonic
saline in bronchiolitis [49�]. Hypothetically, hypertonic
saline may help reverse some of the pathophysiological
abnormalities in bronchiolitis by increasing airway sur-
face thickness, decreasing epithelial edema, improving
elasticity and viscosity of mucus as well as accelerating
mucus transport rates [49�]. Hopefully, the authors’
highly credible rationale for benefit of this agent on
the inflamed airway will translate into clinical effect on
major outcomes such as hospitalization in a large rando-
mized trial.
HelioxThe mixture of helium and oxygen in an 80 : 20 ratio is
much lighter and less dense than air. Because of associ-
ated greater laminar and lower turbulent flow, less respir-
opyright © Lippincott Williams & Wilkins. Unautho
atory effort should be needed for effective breathing [54].
This may be particularly useful in the ICU setting in
combination with the continuous positive airway pressure
management. However, the evidence to date cannot
recommend this intervention for practice. The four stu-
dies performed in this setting are all small, one has no
control group and two lack blinding [55–58]. Although a
recent Cochrane Systematic Review on the subject suggests
that the addition of heliox may significantly reduce
respiratory distress, heliox appears to show no impact
on the rate of intubation or ventilation or the length of
ICU stay [21].
AntibioticsBacteremia rate in febrile infants with bronchiolitis is
very low, at 0.2% [59] – much superceded by urinary tract
infections and otitis media [60,61]. However, antibiotics
should only be used when specific evidence of coexistent
bacterial infection is present [16].
Interestingly, the macrolides appear to have anti-inflam-
matory and immunomodulating properties in addition to
their antibacterial activity. However, the clinical evi-
dence of benefit of this class of drugs in bronchiolitis
is scarce, with disparate results [62,63]. Infants with
severe bronchiolitis requiring assisted ventilation have
been found to have surprisingly high bacterial co-infec-
tion rate in the tracheal secretions, although to what
degree this finding contributes to the clinical manifes-
tation is currently not clear [64]. Although this may be a
fruitful area of future research in this highly select
population, its results are unlikely to impact the vast
majority of infants with bronchiolitis.
RibavirinAlthough ribavirin produces good in-vitro activity against
the viruses causing bronchiolitis, more recent studies
have failed to show its benefit in either the outcomes
of infants admitted to the ICU or the rate of viral
clearance [65,66]. Because this agent may be teratogenic
and is cumbersome to use, the AAP has recently recom-
mended against its routine use [16]. It may be considered
for immunosuppressed infants and those with hemo-
dynamically significant cardiac disease.
MontelukastThe use of montelukast is another example of where
theory promises but treatment does not deliver. Although
infants with bronchiolitis have high levels of pro-inflam-
matory leukotrienes in their airway, a recent randomized
controlled trial of oral montelukast in infants under
2 years of age with acute bronchiolitis over 6 months
failed to reduce subsequent respiratory symptoms [67].
rized reproduction of this article is prohibited.
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Management of bronchiolitis Schuh 113
Continuous positive airway pressureInfants with progressive hypoxemia and increasing
respiratory distress may require continuous positive air-
way pressure support in the ICU setting which constitu-
tes an effective mode of airway support for early venti-
latory decompensation [68,69] and obviates the
complications associated with intubation and sedation
required for children in frank respiratory failure.
Duration of symptoms and return for careRecent evidence suggests that many infants seen in the
ED for bronchiolitis have a protracted clinical course,
with a median disease duration of 15 days, 25% remain-
ing symptomatic after 21 days and 37% experiencing
unscheduled medical visits following the ED visit [70�].
In 2010 Norwood et al. [22�] conducted a study examin-
ing predictors of unscheduled medical visits in infants
with bronchiolitis discharged home from the ED. They
found that the significant independent predictors of this
outcome were age less than 2 months, history of pre-
maturity less than 35 weeks of gestation and history of
hospitalization [22�]. Several years ago, Mansbach et al.[71] also found that the factors associated with a safe
discharge home in bronchiolitis include age 2 months
and older, without prior endotracheal intubation. The
results of these studies are useful in counselling the
parents of this population in the ED prior to discharge
home.
ImmunoprophylaxisPassive immunization with humanized monoclonal anti-
body prophylaxis is recommended for infants 2 years of
age and younger with hemodynamically significant con-
genital heart disease requiring pharmacotherapy, those
suffering from pulmonary hypotension, infants with
chronic lung disease or prematurity who required medical
therapy within 6 months of the start of the bronchiolitis
season and infants born at or before 32 weeks’ gestation,
particularly if they are less than 12 months old during
their first bronchiolitis season [16].
ConclusionThe agents unlikely to impact bronchiolitis outcomes
include systemic corticosteroids alone, inhaled broncho-
dilators alone and antileukotrienes. The most promising
combination to date appears to be that of oral dexametha-
sone and inhaled epinephrine, but numerous related
issues need to be clarified further. These include, among
others, the optimal dose of dexamethasone, duration of
treatment and finding out which subset of babies is the
most likely to respond. Because bronchiolitis is a highly
heterogeneous entity, future research challenges will
include detailed characterization of subjects most likely
opyright © Lippincott Williams & Wilkins. Unauth
to benefit from given interventions. In the meantime,
stick with the good old time-honored supportive route!
References and recommended readingPapers of particular interest, published within the annual period of review, havebeen highlighted as:� of special interest�� of outstanding interest
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rized reproduction of this article is prohibited.