BERSIHAN MUKOSILIAR: TEKNIK

DAN PILIHAN OBAT

UKK Respirology
Indonesian Pediatric Society
 Trakea Main
bronchus

Lobar
bronchus

Segmental
bronchus
Terminal
bronchiolus

Respiratory bronchiolus

Alveolar
duct
Alveolar sacs Alveoli
 24 

Figure 4. Scheme of the airway barrier and the principle of mucociliary clearance.
The tracheal and bronchial portions of mammalian airways are comprised of several
different cell types of which the ciliary cells, the salt and water transporting cells and
 Effect of infection and inflammation
on airway mucosa
• Secretory hyperresponsiveness : goblet cell
and submucosal gland hyperplasia and
hypertrophy  the amount of secreted
mucus increases
• Loss of cells and ciliary function
• Destruction of the surfactant layer by airway
phospholipases
• Alteration of the biophysical properties of
the mucus
 24 

Mucolytic
Expectorant

Mucoregulator
Mucokinetic

Figure 4. Scheme of the airway barrier and the principle of mucociliary clearance.
The tracheal and bronchial portions of mammalian airways are comprised of several
different cell types of which the ciliary cells, the salt and water transporting cells and
 Mucoactive agent
• Expectorant : Increased water volume of mucus and need
good cough and sneezing
Ex. saline hypertonic solution, mannitol, glyceryl guaicolate
• Mucolytic : break the polymer gel
Ex. N-acetylcysteine, dornase alpha, erdosteine
• Mucokinetic : increased ciliary beating frequency and power,
decreased ciliary-mucus adhesion
Ex. Beta-2 agonist, ambroxol
• Mucoregulator : regulate mucus secretion or interfere with
the DNA/F-actin network
Ex. Carbocyteine, anticholinergic
 Hypertonic saline inhalation
• Expectorant : osmotic flow of water from
intracell to ASL
• Mucolytic : break ionic bound between gel
molecule  decrease sputum viscocity
• Provoke cough
• Decrease biofilm production of Ps.
aeruginosa
• Increase glutathione and tyocyanat that have
protective ability to oxidative stress
 Zhang et al. Pediatrics. 2015
Nebulized hypertonic saline for acute bronchiolitis: A systematic review
24 trial, 3209 patients

No significant difference more frequent saline inhalations (3 initial

doses given every 1–2 hours, followed by every 4–6 hours) and
those in which saline solutions were given every 6 to 8 hours

–0.51 days (95% -0.91 to -0.11)

Diagnostic accuracy of bronchiolitis may affect the treatment outcomes
with HS
20% reduction on the risk of hospitalization
 Bali experience
Subanada. 2010
Nebulized hypertonic saline for acute bronchiolitis

Patient : 80 Children with acute bronchiolitis aged < 2 y.o

Intervention : 4 mL NaCl 3% + salbutamol 0,1 mg/kgBW
Comparation : 4 mL NaCl 0,9% + salbutamol 0,1 mg/kgBW
Outcome :
 asthmati
struction
FIGURE2
Ater et al. Pediatrics 2012
Hypertonic saline and acute wheezing in preschool children
impaired
Kaplan-Meier graphfor lengthof stay.
moreimp
Patient : Children with acute wheezing illness aged 1-6 y.o
Intervention : 4 mL hypertonic saline 5% + 2,5 mg albuterol @20 minute for 3 doses
Comparation : 4 mL NaCl 0,9% + 2,5 mg albuterol in the same manner
Outcome :

Wefocus
TABLE4 Hospitalization Rate
effect co
Outcomes HSn=16 NSn=25 PHSvsNS All PatientsN=41
albuterol
Admissionrate(%) 10(62.2%) 23(92%) , .05 33(80%)
apossibl
Dischargedfromthehospital (%) 6(38.8%) 2(8%) 8(20%)
LOS,Median(range) 2(0–5) 3(0–6) , .03 2.7 (0–6) increasin
this has
 Rosenfeld et al. JAMA, 2012
Inhaled hypertonic saline in infants and children younger than 6 years with
cystic fibrosis: the ISIS randomized controlled trial
Patient : Children with CF aged 4-60 m.o
Intervention : 4 mL hypertonic saline 7% @12 hour for 48 weeks
Comparation : 4 mL NaCl 0,9% in same manner
Outcome :
 Elkins et al. NEJM, 2006
A Controlled Trial of Long-Term Inhaled Hypertonic Saline in Patients with Cystic
Fibrosis

Patient : CF aged ≥ 6 years

Intervention : 4 mL hypertonic saline 7% @12 hour for 48 weeks
Comparation : 4 mL NaCl 0,9% in same manner
Outcome :
 Laube et al. BMC Pulm Med 2011
Acute inhalation of hypertonic saline does not improve mucociliary clearance in
all children with cystic fibrosis
Patient : 12 children with CF aged 7-14 y.o Intervention : 5 mL hypertonic saline 7%
Comparation : 5 mL NaCl 0,12% Outcome :
Snijders D et al. Inhaled mucoactive drugs for treating non-cystic fibrosis
bronchiectasis in children. Int J Immunopathol Pharmacol. 2013
 Nicolson et al. Respir Med 2012
The long term effect on inhaled hypertonic saline 6% in non cystic fibrosis
bronchiectasis
Patient : 40 adult bronchiectasis non CF Intervention : 5 mL hypertonic saline 6%
Comparation : 5 mL NaCl 0,9% Outcome :
 SAFETY OF HYPERTONIC SALINE INHALATION
Flores et al. Pediatr Pulmonol 2016
A randomized trial of nebulized 3% hypertonic saline with salbutamol in the
treatment of acute bronchiolitis in hospitalized infants

Patient : 98 children with bronchiolitis aged < 12 m.o

Intervention : 3 mL hypertonic saline 3% + 1,25 mg salbutamol @ 6 h until discharge
Comparation : 3 mL NaCl 0,9% + 1,25 mg salbutamol @ 6 hour until discharge
Outcome :
 Rosenfeld M et al. Pediatr Pulmonol. 2011
Inhaled hypertonic saline in infants and toddlers with cystic fibrosis: short-term
tolerability, adherence, and safety
Rosenfeld et al.

Patient : 20 children with CF aged 12-30 m.o

Intervention : 2 puff albuterol followed within 5-30 mnt with 4 mL hypertonic
Table 2
saline
7% twice daily for 14±2 days Reported Adverse Events
Outcome :

NIH-PA Author Manuscript

N Adverse Event Description

Probably related to treatment

1 increased cough within hour after dose

Possibly related to treatment

1 wheezing after HS: did not pre-treat with albuteroI

1 chapped area around lips

Unrelated to treatment *

4 increased cough

3 rhinorrhea

2 otitis media

2 fever

2 emesis

1 chest congestion

1 eye infection
NIH-PA Author Manu

1 diarrhea

1 influenza

1 lethargy

*
more than one adverse event may have occurred simultaneously in the same participant
 How to delivered saline hypertonic
inhalation therapy
The patient can perform The patient can’t perform
reliable spirometry test reliable spirometry test
• Baseline PFT • Assess for wheeze, HR, SaO2
• Administer salbutamol (200 prior to test dose
microgram by MDI ±spacer or • Administer salbutamol
by nebulizer) • Administer hypertonic saline
• Post bronchodilator PFT nebulisation
• Administer hypertonic saline • During nebuliser and for 15
nebulisation minutes afterwards monitor HR,
• Perform 15 minute post SaO2, wheeze, signs of
hypertonic saline spirometry respiratory distress
• Cease if the patient has signs of
respiratory distress and
administer inhaled salbutamol if
required
 Mannitol
• Expectorant : increased osmotic gradient 
water influx to airway that increased ASL
• Mucokinetic : released mediator that
stimulate ciliary beating frequency
• Mucolytic : break hydrogen bond between
mucin  viscocity decrease
 Bilton et al. J Cyst Fibros 2013
Pooled analysis of two large randomized phase III inhaled mannitol studies in
cystic fibrosis

Patient : 600 CF aged ≥ 6 years with FEV1 40-89%

Intervention : 400 mg mannitol DPI twice daily for 26 weeks
Comparation : 50 mg mannitol DPI in the same manner
Outcome :

Forest plot of FEV1 % change of % predicted Forest plot of FVC % change of % predicted
Preconditional before using mannitol :
- Already pass mannitol tolerance test
- Bronchodilator prior to mannitol inhalation
- Baseline data before and monitoring during and after
mannitol inhalation (the same like hypertonic saline
inhalation)
 Glyceryl guaicolate
• Stimulate cholinergic pathway
• Increases mucus secretion from submucosa
gland  viscocity decreased
• Decreases sensitivity of cough reflex
• The only expectorant that approved by FDA
as OTC
• Dosage: 50-100 mg for 2-5 y.o, 100-200 mg
for 6-11 y.o, and 200-400 mg for ≥ 12 y.o @ 4
hour
• Not enough evidence for use or against
glyceryl guacolate as therapy in children
Smith et al. Over-the counter (OTC) medications for acute cough in children and
adults in community settings. Cochrane Database Syst Rev. 2014

Paul IM. Therapeutic options for acute cough due to upper respiratory infections in
children. Lung. 2012
 Beta 2 agonist
• The main indication are for airway
obstruction due to bronchial hyperreactivity
• Effect on mucocilliary clearance:
– Stimulate β2 receptor  increased cilicary
beating frequency
– Increased cAMP
– Bronchodilatation increases expiratory flow 
increases cough effectivity
• Cochrane reviews on SABA (Franco 2003) and
LABA used as monotherapy for people with
bronchiectasis (Sheikh 2001) found no
eligible studies
• No high quality studies that approved
longterm efect of bronchodilator on
bronchiectasis  the use should based on
whether there are bronchial hyperreactivity
and side effect
 Goyal et al. Cochrane Database Sust Rev. 2014
Combination inhaled corticosteroids and long-acting beta2-agonists for children
and adults with bronchiectasis
Cough-free days
A significant difference
Studies between
: one singlegroups
studywas
onreported for cough-
40 non-CF bronchiectasis non asthmatic aged 18-80 y.o
freedays; those in thecombined ICS-LABA group had 15.3% of
no studies on children
dayscough-freecompared with 3% in theICSgroup (MD 12.30,
Intervention : 640 μg of budesonide and 18 μg of formoterol for 3 months
95% CI 2.38 to 22.2; Analysis1.3, Figure 5).
Comparation : high-dose budesonide dipropionate (1600 μg/day)
Outcome :
Figure 5. Forest plot of comparison: cough-free days.

No significant difference for QO, lung function, number of participants with one
or more exacerbations or adverse events. Given the high risk of bias and the
small number of participants in the single included study, widespread
applicability of these results is substantially limited.
Exacerbations
No significant differencein thenumber of participantswho expe-
rienced exacerbations was reported (seven in the ICS group and
four in theICS-LABA group). No significant differencesin hospi-
talisation weredescribed between groups(OR 0.26, 95% CI 0.02
to 2.79; Analysis1.4, Figure6). Wedid not includeexacerbations
 Becker et al. Cochrane Database Syst Rev 2015
Beta2-agonists for acute cough or a clinical diagnosis of acute bronchitis
Analysis 1.8. Comparison 1 Beta2-agonists versus placebo in children, Outcome 8 Mean cough score after
seven days.

Review: Beta2-agonistsfor acute cough or a clinical diagnosis of acute bronchitis

There is no evidence that beta2-agonists are useful in healthy children who
Comparison: 1 Beta2-agonists versus placebo in children
have an acute cough, particularly if their lung examination is normal and no
Outcome: 8 Mean cough score after seven days
evidence of airflow restriction .
Std. Std.
Mean Mean
Study or subgroup Beta2-agonist Placebo Difference Difference
N Mean(SD) N Mean(SD) IV,Fixed,95%CI IV,Fixed,95%CI

Bernard 1999 23 10.1 (1.7) 23 10.1 (2.2) 0.0 [ -0.58, 0.58 ]

-1 -0.5 0 0.5 1
Favours beta2-agonist Favours placebo

These children are more likely to have adverse effects (shaking, tremor,
tachycardia) than to derive any clinical benefit

There is a particular need for identifying clinical characteristics that can predict
who might benefit
Beta2-agonists for acute cough or a clinical diagnosis of acute bronchitis (Review) 30
Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
 Ambroksol
• Stimulated surfactant and mucus
(secretolytic)  normalized mucus viscocity
• Antiinflammation
• Antioxidant
 Yang F. Pak J Pharm Sci 2015
Oxygen-driving and atomized mucosolvan inhalation combined
with holistic nursing in the treatment of children severe bronchial
pneumonia

7,5 mg ambroxol dilute with 5 mL normal saline for severe pneumonia  cure rate
very different (60% vs 36,67%) but not statistically significant (p > 0,05)

Wang et al. APMIS. 2016

Ambroxol inhibits mucoid conversion of Pseudomonas aeruginosa
and contributes to the bactericidal activity of ciprofloxacin against
mucoid P. aeruginosa biofilms
In vitro research : ambroxol with ciprofloxacin work synergistically to prevent non-
mucoid to mucoid change of biofilm mediated by H2O2. This effect related with
antioxidant activity of ambroxol
 N-acetyl sistein
• Break disulfide bond of mucus
• Because it is acetylized form of L-cysteine as
major precursor of gluthathione as major
antioxidant
• Decrease pro inflammatory cytokine like IL-9
and TNFα with vasodilator effect which
increases c-GMP and regenerated
endothelial-derived relaxing factor
 Naz et al. J Col Pshy Surgeon Pakitan 2014
Effectiveness of nebulized N-Acetylcysteine solution in children with acute
bronchiolitis

Patient : Acute viral bronchiolitis aged 2 - 24 months

Intervention : Nebulization 20 mg N-acetylcysteine in 3 ml of 0.9% saline
Comparation : Nebulization 2.5 mg salbutamol in 3 ml of 0.9% saline solution
Farrah Naz, Afsheen Batool Raza, Iftikhar Ijaz and Muhammad Yaqoob Kazi
Outcome :
until discharge. One
observation may be tha
clearance of the respi
breathing, as occurred in
of secretions might h
secondary bacterial grow
shortening of hospital st
Similarly, other studie
mucolytic agents (hype
dilators produce mode
clinical scores. 15,20,21
weighed against the co
controversial role, the
Figure 1: Graph showing the number of days stay in hospital. widespread, with some
80% bronchiolitis patien
4.36 ± 1.66 days. Minimum duration of stay was 24 Bronchodilators are ag
 Conrad C et al. J Cystic Fibrosis. 2015
Long-term treatment with oral N-acetylcysteine: affects lung function but not
sputum inflammation in cystic fibrosis subjects. A Phase II randomized placebo-
controlled trial.

Patient : CF patient aged 9 – 59 y.o

Intervention : 900 mg N-acetylcysteine dissolved in liquid 3x daily for 24 weeks
Comparation : placebo in same manner
Outcome :
 Dornase alpha
• Proteolytic enzime that break DNA that
released by degenerated neutrophil. In huge
number, DNA could increase viscocity of the
mucus
 Rozov et al. Rev Paul Pediatr 2013
A first-year dornase alfa treatment impact on clinical parameters of patients
with cystic fibrosis: The Brazilian cystic fibrosis multicenter study

Patient : 152 CF patient 6-11 y.o, from 16 CF reference centers

Intervention : Dornase alpha for 1 year
Outcome :
 Konstan et al. Pediatr Pulmonol 2011
Clinical use of dornase alpha is associated with a slower rate of FEV1 decline in
cystic fibrosis

Patient : CF patient 11.8 y.o

Intervention : dornase alpha
Comparation : no treatment
Outcome :
 Erdosteine
• Increased mucus production
• Increased mucociliary transport
• Most of the study about erdosteine in
children are acute respiratory tract ds
• Study on erdosteine use in chronic
respiratory disease from adult population
 Unuvar et al. Acta Paediatr 2010
Effectiveness of erdosteine, a second generation mucolytic agent, in children
with acute rhinosinositis: a randomized, placebo controlled, double-blinded
clinical study
Patient : acute rhinosinusitis children 3 - 12 y.o
Intervention : erdosteine 5-8 mg/kgBW/d
Comparation : placebo
Outcome :
 Tutanc et al. Hum Exp Toxicol 2012
Effects of erdosteine on homeostasis: an experimental study

Study : Rats in group I : 0.5 cc of normal saline daily through oral gavage for 3 days
Group II Erdosteine 3 mg/kg/day
Group III 10 mg/kg/day
Group IV 30 mg/kg/day
Outcome :
 S-carboxymethylcysteine
• Increased cyalomucine synthesis  less
viscous part of mucus
• Increased chloride transport across airway
epithel  mucoregulator
• Decreased neutrophil infiltration to airway
lumen  decreased IL-8 and IL-6
• Prevent attachment of virus and bacteria to
ciliated cell
 Chalumeau et al. Cochrane Database Syst Rev 2013
Acetylcysteine and carbocysteine for acute upper and lower respiratory tract
infections in paediatric patients without chronic bronchopulmonary disease

• Based on a limited number of patients included in studies

whose methodological quality was questionable which dated
1970-1980
• Acetylcysteine and carbocysteine are prescribed for self limiting
diseases (ex. acute cough, bronchitis)
• Millions of paediatric patients are exposed to these drugs each
year in many countries
• Some benefits on frequency, intensity and duration of
symptoms, and appear to be safe in children older than two
years
• Regarding children younger than two years old, there are
current strong concerns about the safety of acetylcysteine and
carbocysteine
 Mallet et al. PLoS One 2011
Respiratory paradoxical adverse drug reactions associated
with acetylcysteine and carbocysteine use in peediatric
patients: a national survey

• 1989 – 2008  139 cases of ADRs in children (all < 6 years) due to
mucolytic drug
• Mean age 8.6 m.o (median 5 m.o, range 3 weeks - 34 m.o)
– 6 children (10%) neonates
– 34 (58%) < 6 m.o
– 46 (78%) < 1 y.o
– 11 (19%) 1 - 2 y.o
– 1 : > 2 y.o
• The mean weight was 7.9 kg (median 7 kg, range 3.1–18 kg). One
patient had a severe underlying condition (broncho-pulmonary
dysplasia); 9 children (15%) had a relevant medical history prior to
the current episode that led to mucolytic drug use: bronchiolitis (n
= 8, 14%), asthma (n = 1).
• Type of medicine : 30 (51%) carbocysteine, 28
(48%) acetylcysteine, and 1 received 2 drugs
simultaneously
• The mean duration of treatment before the
beginning of the ADR was 5.9 days (median 4
days; range 2–39 days)
• 4 (7%) without prescription
• Dosage : Carbocysteine mean dosage 23
mg/kg per day. Acetylcysteine 27 mg/kg per
day
• Type of complications :
– 35, 59% worsening of respiratory distress during
bronchiolitis
– 19, 32% increased bronchorrhea
– 18, 31% dyspnoea
– 14% cough aggravation or prolongation
– 19% bronchospasm (n = 1).
 Anticholinergic
• Blocking cholinergic pathways that normally
is active stimulus of airway mucus
• The use is usually in combination with β2
agonist in and only when there’s proved of
clinical benefit
• The reported adverse event is increased
arrythmia (adj OR 1,56; 95%CI 1,08-2,25)
 Airway clearance technique
• Active cycle of breathing technique (ACBT)
• Chest physiotherapy
• Forced exhalation technique
• High-frequency chest wall compression
• Intrapulmonary percussive ventilation
• Mechanical insufflation-exsufflation
• Positive expiratory pressure
 Lee et al. Cochrane database of systematic review 2014
Airway clearance techniques for bronchiectasis

Analysis 2.1. Comparison 2 Stable bronchiectasis: chest physiotherapy ACT vs no ACT (control), Outcome
1 Change in HRQoL.

Review: Airway clearance techniquesfor bronchiectasis

Comparison: 2 Stable bronchiectasis: chest physiotherapy ACT vs no ACT (control)

Outcome: 1 Change in HRQoL

Mean Mean
Study or subgroup Experimental Control Difference Difference
N Mean(SD)[points] N Mean(SD)[points] IV,Fixed,95%CI IV,Fixed,95%CI

Nicolini 2013 10 0.4 (6.8) 10 9.9 (3.6) -9.50 [ -14.27, -4.73 ]

-10 -5 0 5 10
Favours ACTs Favours control
 AARC recommendation
• For non CF hospitalized
– Not routinely indicated for pneumonia without
complication
– ACT not routinely indicated if the patient can
mobilize secret with cough. For these patients 
effective cough technique
• Neuromuscular disorder with muscle weakness
and weak cough flow (<270 L/mnt)  not
routinely recommended
• Post operation : early mobilization to decrease
complication
 Take home message
• The need for mucoactive agent must be
balanced between the theory and actual proved
of benefit
• Beside effectivity, the side effect should be
consider especially in longterm use
• Treat the underlying disease
• Know what to treat, monitor the side effect and
prepared for side effect management
• No mucoactive agent for all disease, adjust with
individual patient response
TERIMA KASIH