ORIGINAL ARTICLE

Effectiveness of Nebulized N-Acetylcysteine Solution

in Children with Acute Bronchiolitis
Farrah Naz, Afsheen Batool Raza, Iftikhar Ijaz and Muhammad Yaqoob Kazi

ABSTRACT

Objective: To evaluate the effectiveness of nebulized mucolytic therapy (N-acetylcysteine) in treatment of children with
acute bronchiolitis.
Study Design: Prospective randomized, controlled study.
Place and Duration of Study: Paediatric Medical Unit of the Children's Hospital and the Institute of Child Health, Lahore,
from November 2011 to April 2012.
Methodology: All the patients aged 2 months to 24 months, with the diagnosis of acute viral bronchiolitis were enrolled
in the study. A predesigned proforma was completed after taking parental consent. All eligible patients were randomly
assigned to one of the two groups: group-1 received N-acetylcysteine in nebulized form, and group-2 received salbutamol
as a nebulized aerosol. Both groups were then compared regarding their clinical improvement and duration of stay in the
hospital. The data obtained was analyzed on the statistical software SPSS version 16. Descriptive statistics were obtained
by frequencies and percentages. Chi-square test was applied to find p-value.
Results: A total of 100 patients met the inclusion criteria. The mean age was 3 months. On the first day of treatment, the
mean clinical severity score at baseline were 5.38 2.62 in group-1 and 4.68 2.2 in group-2. At day 3 and 5, it was 2.9
1.48 and 3.30 1.77 in group-1 and 0.88 1.08 and 1.90 1.32 in group-2 respectively. The clinical severity score after
N-acetylcysteine inhalation therapy was better in group-1 on the third but more so on fifth day after hospital admission.
The mean duration of hospitalization was 4.67 2.2 days for the whole population and it differed between the 2 groups:
4.36 1.66 days in group-1 versus 4.98 2.6 days in group-2.
Conclusion: On the basis of improvement in clinical severity score and early discharge from the hospital, N-acetylcysteine
was found to be an effective therapy in acute bronchiolitis.
Key Words: N-acetylcysteine (NAC). Bronchiolitis. Clinical severity score (CS score).

INTRODUCTION

Viral bronchiolitis is the most common reason for

hospital admission in infants, accounting for 20% of
hospitalization at < 1 year of age.1 Bronchiolitis usually
affects children younger than 2 years, with a peak in
infants aged 2 - 5 months. Its incidence peaks between
December and March.2
Respiratory syncytial viruses are the main cause of
bronchiolitis worldwide and can cause up to 70 or 80%
of lower respiratory tract infections during high season.3
The recently discovered human metapneumo-virus and
other viruses like adenovirus, parainfluenza virus type-3,
influenza virus and rhinovirus also cause bronchiolitis
that is indistinguishable from RSV disease.3,4
It is more common in males, those who are not breast
fed and living in crowded conditions. Older family
members are also a common source of infection. Infants
who are breastfed with colostrum rich in immunoDepartment of Paediatric Medicine, The Children's Hospital
and Institute of Child Health, Lahore.
Correspondence: Dr. Farrah Naz, 120-U, Street No. 3,
Phase II, DHA, Lahore.
E-mail: farrahnaz09@gmail.com

Received: March 26, 2013; Accepted: December 30, 2013.

408

globulin-A (IgA) appear to be relatively protected from

bronchiolitis.5,6

Pathophysiologically, bronchiolitis is an infection of the

bronchiolar epithelium with subsequent profound
submucosal and advential oedema, increased secretion
of mucus, peribronchiolar mononuclear infiltration and
epithelial cell necrosis. These changes obstruct flow in
the small airways leading to hyperinflation, atelectasis
and wheezing.7

Because of the high incidence of disease among

children, different treatment modalities have been in
practice for some years but there is no effective specific
treatment for bronchiolitis.8 Controversies exist over the
available treatment for acute bronchiolitis. Current
clinical practice guidelines do not recommend the
routine use of any medication for bronchiolitis.9 Therapy
is principally supportive, despite the evidence, use of
ineffective therapies for bronchiolitis remains high.10,11
Some of these therapies are specific to the virus e.g.
ribavirin, others are symptomatic like bronchodilators
and corticosteroids. Most of the studies using
glucosteroids in the treatment of bronchiolitis denied a
positive therapeautic effect in previously normal
children.4,7
N-acetylcysteine is an antioxidant, antimucus compound
that increases intracellular glutathione at the cellular

Journal of the College of Physicians and Surgeons Pakistan 2014, Vol. 24 (6): 408-411

Effectiveness of nebulized N-acetylcysteine solution in children with acute bronchiolitis

level. It cleaves disulfide bonds by converting them to

two sulfhydryl groups. This action results in the breakup
of mucoproteins in lung mucus, reducing their chain
lengths and thinning the mucus, mucolytics like NAC
has been studied in the treatment of various disease
states, including those pulmonary in nature such as
cystic fibrosis, chronic bronchitis, non-cystic fibrosis
bronchiectasis, bronchiolitis, most recently idiopathic
pulmonary fibrosis, as well as numerous critically ill
states.12,13
With this background knowledge, the purpose of this
study was to evaluate the effectiveness of nebulized
mucolytic therapy in treatment of children with viral
bronchiolitis.

METHODOLOGY

This prospective randomized, controlled study was done

at the paediatric medical unit of The Children's Hospital
and Institute of Child Health, Lahore, form November
2011 to April 2012. All the patients aged 2 to 24 months
with the provisional diagnosis of acute viral bronchiolitis
were enrolled. An inclusion criterion was a prodromal
history consistent with upper respiratory tract infection
followed by wheezing and/or crackles on auscultation
and a clinical severity score of > 4,14 on presentation.
Any patient who was found to have underlying bronchopulmonary dysplasia, chronic lung disease, neuromuscular impairment, immunodeficiency or congenital
heart disease was excluded from the study. A
predesigned proforma was filled after taking parental
consent. The proforma included a detailed history
showing their demographic data, duration of illness,
presenting complaints, clinical signs, laboratory results,
interventions (if required) and outcome.
All patients fulfilling the inclusion criteria were randomly
assigned to one of the two groups: group-1 received
20 mg N-acetylcysteine in 3 ml of 0.9% saline in
nebulized aerolized form; group-2 received inhalation of
2.5 mg salbutamol in 3 ml of 0.9% saline solution as a
nebulized aerosol. Patients in each group received 3
treatments every day, delivered at intervals of 8 hours for
5 days. Patients were examined on admission and every
morning for severity of disease. For assessing improvement, clinical severity score was used. Both groups were
compared regarding their duration of stay in hospital and
clinical improvement. These patients were followed till
their discharge from hospital.

The discharge was based on the criteria of SaO2%

> 95%, taking orally and normal respiratory rate (< 50 for
infants aged 2 months-1 year, < 40 for 1 - 2 years).
The data obtained was analyzed on the statistical
software Statistical Package for Social Sciences (SPSS)
version 16. Descriptive statistics were obtained by
frequencies and percentages and Chi-square test was
applied to find p-value.

RESULTS

One hundred and five patients met the inclusion criteria

for the study. Five patients were excluded; one because
of bronchopulmonary dysplasia, 3 due to congenital
heart disease and one due to spinomuscular atrophy
(SMA). Out of the total 100 patients, 50 were randomly
assigned to group-1 and 50 to group-2. The mean age
was 3 months. Amongst them, 40% were male and
60% female. The two groups had similar clinical
characteristics and variables at baseline (Table I).

Clinical parameters were assessed using a CS score

shown in Table II. On the first day of treatment, the mean
clinical severity score at baseline were 5.38 2.62 in
group-1 and 4.68 2.2 in group-2. At days 3 and 5, it
was 2.90 1.48 and 0.88 1.08 in group-1 and 3.30
1.77 and 1.90 1.32 in group-2 respectively. The rate of
decrease in clinical severity score after inhalation
therapy depicting response of the patient was better in
group 1 on the third but more so on fifth day after
hospital admission (Figure 1).

Duration of hospital stay is shown in Table III. The mean

duration of hospitalization was 4.67 2.2 days for the
whole population and it differed between the two groups:
4.98 2.6 days in group-2, whereas patients treated with
nebulized N-acetylcysteine were discharged sooner,
Table I: Clinical characteristics of the two groups.
Characteristics

Group-1

Group-2

Male / female ratio

60 / 40

68 / 32

Age (months)

3.6

3.2

Baseline clinical severity score

5.38 2.62

4.68 2.2

Days of illness at hospital admission

5.2 2.62

5.5 1.90

Mean oxygen saturation

90.67%

90.61%

Table II: Clinical severity score (from Wang et al14).

Variables

None

Terminal expiratory Entire expiration

breaths/min < 30
Wheezing

Score

31 - 45

or only with

or audible on

stethoscope
Retraction

None

Intercostal only

General

Normal

condition

Total

Journal of the College of Physicians and Surgeons Pakistan 2014, Vol. 24 (6): 408-411

Inspiration and

expiration

without

Tracheosternal

Severe with

Irritable,

stethoscope

nasal flaring

lethargic, poor
feeding

Less than

Group-2

> 60

expiration without

stethoscope

Table III: Duration of hospitalization.

Group-1

46 - 60

5 days
31

Greater than
5 days
19

Total

p-value

50

0.108

(62.0%)

(38.0%)

(100%)

(46.0%)

(54.0%)

(100%)

(54.0%)

(46.0%)

(100%)

23

54

27

46

50

100

409

Farrah Naz, Afsheen Batool Raza, Iftikhar Ijaz and Muhammad Yaqoob Kazi

until discharge. One possible explanation for this

observation may be that mucolytic agents assist in the
clearance of the respiratory secretions and improve
breathing, as occurred in this study. This early clearance
of secretions might have reduced opportunity for
secondary bacterial growth and thereby contribute to the
shortening of hospital stay.

Figure 1: Graph showing the number of days stay in hospital.

4.36 1.66 days. Minimum duration of stay was 24

hours and maximum was 8 days in group-1, while it
was 2 and 17 days in group-2. Although duration of
hospital stay among children in group-1 was shorter but
this difference did not attain statistical significance
(p=0.108).

DISCUSSION

In Pakistan, respiratory infections are one of the major

killers. Acute bronchiolitis is amongst the most common
lower respiratory tract infections in infants.15 Although
most children who have bronchiolitis do well and have
an uncomplicated disease with a self-limited course, for
some, it is a serious and sometimes life-threatening
illness.16 In this study, there was male predominance
(60%) which is in accordance with other studies.3,17 The
presently reported patient population had a mean age of
3 months which is also similar to other studies.4,15

This hospital based study demonstrates that acetylcysteine inhalation reduced the length of stay in children
hospitalized with acute bronchiolitis. This has a clinically
relevant benefit with the potential for widespread impact
on the treatment of bronchiolitis. N-acetylcysteine is a
relatively inexpensive drug available in intravenous, oral
and inhaled formulations. It is acetylated form of Lcysteine, which serves as a major precursor to the
antioxidant glutathione. It reduces the formation of
proinflammatory cytokines, such as IL-9 and TNF- and
also has vasodilator properties by increasing cyclic GMP
levels and by contributing to the regeneration of
endothelial-derived relaxing factor.18 Researchers in
Switzerland have reported that prolonged use of NAC as
a dietary supplement prevents acute exacerbations of
chronic bronchitis.19
In this study, an improvement in clinical severity score
after N-acetylcysteine inhalation as compared to
salbutamol, a bronchodilator, for improving the
bronchiolitis severity scores in patients was observed.
The clinical severity scores after mucolytic inhalation
decreased progressively in a significant way each day
410

Similarly, other studies shows better results with

mucolytic agents (hypertonic saline), while bronchodilators produce modest short-term improvement in
clinical scores.15,20,21 This small benefit must be
weighed against the costs of these agents. Despite its
controversial role, the use of bronchodilators remains
widespread, with some reporting its use in more than
80% bronchiolitis patients.4

Bronchodilators are agents often used as aerosols to

widen the air passages by relaxing the bronchial muscle.
They are effective in helping infants and adults with
asthma. However, unlike asthmatics, infants with
bronchiolitis are usually wheezing for the first time and
wheezing for a different reason, that is to say, because
their airways are clogged with debris. Therefore, infants
with bronchiolitis may be less likely to respond to
bronchodilators.22 The response with bronchodilator was
poor in this study also.
In present study, nebulized N-acetylcysteine produced a
16% reduction (0.62 days) in the mean length of hospital
stay among infants hospitalized with viral bronchiolitis.
This percentage reduction in hospital stay is low when
compared with other studies where hypertonic saline is
used, 26% in study by Brian et al.4 and 25% reduction
seen by Mandelberg et al.23 Inhalation of hypertonic
saline has its own adverse effects, it may cause
bronchoconstriction in asthmatics,4 and co-administration
with a bronchodilator is often recommended.23 Further
studies are required to confirm these findings so that this
simple, safe and apparently effective treatment could be
generalized in clinics and hospitals caring for paediatric
patients.

N-acetylcysteine was used in this study and no adverse

effects were noted, which is in concordance with
excellent safety profile reported by others.13,19 Given the
clinically relevant benefit and good safety profile,
nebulized N-acetylcysteine use can be considered an
effective and safe treatment for infants with viral
bronchiolitis.
This study has some limitations; the relatively small
number of patients enrolled, did not allow to clearly
distinguish the efficacy of N-acetylcysteine in a definitive
way. The bronchiolitis severity score was objectively
determined but the examiner was not blinded with
respect to the treatment; this could generate a bias.
Further studies, preferably multi-centered, are required
to evaluate the effectiveness of this therapy.

Journal of the College of Physicians and Surgeons Pakistan 2014, Vol. 24 (6): 408-411

Effectiveness of nebulized N-acetylcysteine solution in children with acute bronchiolitis

CONCLUSION

On the basis of an improvement in clinical severity score

and early discharge from the hospital, N-acetylcysteine
was found to be an effective therapy in acute
bronchiolitis.

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