Update Recommendation of

UKK Respirology on
Nebulization Treatment in
Children with
Acute Asthma
Heda Melinda N Nataprawira
Professor of Pediatric
UKK Respirologi-PP IDAI

Presented in Symposium and Webinar Meeting “Update on Nebulization Treatment in Children with Acute Asthma
and Strategy to Control Asthma”. Jakarta, 10 Maret 2019
 Prof. Dr. dr. Heda Melinda Nataprawira, Sp.A(K) M.Kes
Staff Department of Child Health
Faculty of Medicine – Universitas Padjadjaran

Previous and Current Posts and Position

- Pediatric Respirology Consultant, Professor in Department
of Pediatrics Faculty of Medicine – Universitas Padjadjaran
- Secretary of Doctoral Program Faculty Of Medicine –
Universitas Padjadjaran Bandung Indonesia (up to 2012)
- Reviewer Several Journal (International and National
Journal)
- Contributing Editor Paediatrica Indonesiana since 2004 up
to now
- Author and Co-author International and National Journal
Education
Medical Doctor : Faculty of Medicine Universitas Padjadjaran
Pediatric Residence : Faculty of Medicine Universitas Padjadjaran
Fellowship in Respirology : Nijmegen – Radboud University Nijmegen (Academisch
Ziekenhuis) The Netherland
Health Magister : Faculty of Medicine Universitas Padjadjaran
PhD Program : Faculty of Medicine Universitas Padjadjaran
 OUTLINE
1. Overview Asthma and Treatment of Acute
Asthma
2. Overview Corticosteroid in the Treatment of
Asthma
•Cellular Effects of Glucocorticoids
•Actions of ICS
3. Budesonide Inhalation
4. Efficacy and Safety of Budesonide in Asthma
Exacerbation in Children (Studies Results)
5. Result of Advisory Board Meeting of Respirology
Coordination Working Unit
 ASTHMA
Heterogeneous disease, characterized by
chronic airway inflammation

Despite
Historymajor advancessymptoms
of respiratory in the treatment
such as of asthma
wheeze,
shortness
and the development of several
of breath, chest asthma
tightness guidelines
and cough that ,
vary over time250,000
approximately and in intensity,
people dietogether with each
prematurely
variable
year fromexpiratory
asthma airflow limitation

GINA; 2018.
WHO; 2007.
 ASTHMA
Recurrent exacerbation
chronic airway with wheezing, chest
inflammation tightness, cough

Frequent of
Early initiation emergency
inhaledvisitcorticosteroid
and
(ICS) is highly hospitalisation
effective reducing asthma
symptoms, risk of exacerbations,
hospitalization, and death
 Classification of Asthma

Asthma Severity
Level Asthma Control
Asthma Exacerbation

GINA; 2018.
PNAA; 2016.
 Asthma Exacerbation
Mild or L i fe -
S eve re
Moderate t h re a t e n i n g
- Talk in phrases - Talk in words - Drowsiness
- Prefer sitting to - Sits hunched - Lethargic
lying forwards - Unheard breath
- Not agitated - Agitated sound
- Respiratory rate - Respiratory rate
increased >30/min
- Accessory muscle - Accessory muscle
not used being used
- Pulse rate 100-120 - Pulse rate >120
bpm bpm
- O2 saturation - O2 saturation
(room air) < 90- (room air) < 90%
95% - PEF 50% predicted
or best

GINA; 2018.
 Asthma Exacerbation
Mild-Moderate
Severe
Life-threatening

PNAA 2016
Mild
PNAA Moderate
2004
Severe
 Asthma Exacerbation
2017 2016 2015 2014

Mild or Moderate
Severe
Life-threatening
2012
Mild Moderate
Severe Respirator y
Arrest Imminent
GINA; 2012–2017.
Management of Acute Asthma in
GINA 2018

P r i m a r y C a re
C h i l d ≤ 5 ye a r
Setting
A c u t e C a re Adult, Adolescent,
Setting (EMG) 6 −1 1 ye a r s
 PRIMARY CARE Children presents with acute or sub-acute asthma exacerbation or acute wheezing episode

Consider other diagnosis

ASSESS the CHILD Risk factor for hospitalization
Severity of exacerbation?

MILD or MODERATE
• Breathless, agitated SEVERE OR LIFE THREATENING
• Pulse rate ≤ 200 bpm (0-3 yrs) or ≤ 180 bpm (4-6 • Unable of speak or drink
yrs) • Central cyanosis
• Oxygen saturation ≽ 92% • Confusion or drowsiness
• Marked subcostal and/or subglottic retractions
START TREATMENT • Oxygen saturation < 92%
Salbutamol 100 mcg 2 puffs by pMDI + spacer or 2.5 mg by nebulizer • Silent chest on auscultation
Repeat every 20 min for the first hour if needed • Pulse rate > 200 bpm (0-3 yrs), or >180 bpm (3-5yrs)
Controlled oxygen (if needed and available) target saturation 94-96% urgent

MONITOR CLOSELY for 1-2 hours TRANSFER TO ACUTE CARE FACILITY

Transfer to high level care if any of: worsening While waiting: give inhaled SABA and
Lack of response to salbutamol over 1-2 hrs
Any signs of severe exacerbation ipratropium bromide, O2 systemic
Increasing respiratory rate corticosteroid
Decreasing oxygen saturation

CONTINUE TREATMENT IF NEEDED

Monitor closely as above
If symptoms recur within 3-4 hrs Worsening/failure to respond
- Give extra salbutamol 2-3 puff per hour to salbutamol 10 puff
- Give prednisolone 2mg/kg max. 20 mg for <2yrs; max. 30 mg for 2-5 yrs) only

DISCHARGE/FOLLOW-UP PLANNING
Ensure that resources at home are adequate
Reliever: continue as needed
Management of Acute
Controller: consider need for adjustment, regular controller
Check inhaler technique and adherence
Follow up within 1-7 days
Asthma in Primary Care
Provide and explain action plan

FOLLOW UP VISIT
Setting ≤ 5 yrs
Reliever: reduce to as needed
Controller: continue or adjust depending on cause of exacerbation, and duration of need for extra salbutamol
(2018) GINA; 2018.
Risk factor: check and correct modifiable risk factors that may have contributed to exacerbation, including inhaler technique and adherence
Action plan: is it understood? Was it used appropriately? Does it need modification?
Schedule next follow up visit
 PRIMARY CARE Patient presents with acute or sub-acute asthma exacerbation

Is it asthma?
ASSESS the PATIENT Risk factors for asthma-related death?
Severity of exacerbation?

MILD or MODERATE SEVERE

• Talk in phrases • Talk in words LIFE-THREATENING
• Prefer sitting to lying • Sits hunched forwards Drowsy, confused or silent chest
• Not agitated • Agitated
• Respiratory rate increased • Respiratory rate >30/min
• Accessory muscle not used • Accessory muscle being used
• Pulse rate 100-120 bpm • Pulse rate >120 bpm
• O2 saturation (room air) 90-95% • O2 saturation (room air) < 90% urgent
• PEF 50% predicted or best
START TREATMENT
SABA 4-10 puffs by pMDI + spacer, repeat every
20 minutes for 1 hour TRANSFER TO ACUTE CARE FACILITY
Prednisolone: adults 1 mg/kg max 50 mg, worsening While waiting: give inhaled SABA and
children 1-2 mg/kg max 40 mg ipratropium bromide, O2 systemic
Controlled oxygen (if available): target corticosteroid
saturation 93-95% (children 94-96%)

CONTINUE TREATMENT with SABA as needed

ASSESS RESPONSE AT 1 hour (or earlier) worsening
ASSESS FOR DISCHARGE Management of Acute Asthma in
ASSESS AT DISCHARGE
Symptom improved, not needing SABA Reliever: continue as needed
PEF improving and 60-80% of personal best or predicted Primary Care Setting
Controller: start, step up, check inhaler technique, adherence
Oxygen saturation >94% room air Prednisolone: continue, usually for 5-7 days (3-5 days for children)
Resources at home adequate Adult, Adolescent, 6–11 yrs
Follow up: within 2-7 days

FOLLOW UP
Reliever: reduce to as-needed
(2018)
Controller: continue higher dose for short term (1-2weeks) or long term (3 month), depending on background to exacerbation
Risk factor: check and correct modifiable risk factors that may have contributed to exacerbation, including inhaler technique and adherence GINA; 2018 .
Action plan: is it understood? Was it used appropriately? Does it need modification?
 INITIAL ASSESSMENT Are any of the following present?
A: airway B: breathing C: circulation Drowsiness, Confusion, Silent chest
no yes
Further TRIAGE BY CLINICAL STATUS
According to worst feature
Consult ICU, start SABA and O2
yes
no

MILD or MODERATE SEVERE

• Talk in phrases • Talk in words
• Prefer sitting to lying • Sits hunched forwards
• Not agitated • Agitated
• Respiratory rate increased • Respiratory rate >30/min
• Accessory muscle not used • Accessory muscle being used
• Pulse rate 100-120 bpm • Pulse rate >120 bpm
• O2 saturation (room air) 90-95% • O2 saturation (room air) < 90%
• PEF 50% predicted or best
Short-acting beta agonist Short-acting beta agonist
Consider ipratropium bromide Consider ipratropium bromide
Controlled O2 to maintain saturation 93-95% Controlled O2 to maintain saturation 93-95%
(children 94-98%) (children 94-98%)
Oral corticosteroid Oral or IV corticosteroid
Consider IV magnesium
Consider high dose ICS

If continuing deterioration, treat as

severe and re-assess for ICU

ASSESS CLINICAL PROGRESS FREQUENTLY Management of Acute Asthma

MEASURE LUNG FUNCTION
in Acute Care Setting (EMG)
In all patients one hour after initial tretament

FEV1 or PEF 60-80% of predicted or personal best and

Adult, Adolescent, 6–11 yrs
FEV1 or PEF <60% of predicted or personal best, or lack of
symptoms improved
MODERATE
clinical response
SEVERE (2018)
Consider for discharge planning Continue treatment as above and reassess frequent GINA; 2018.
Management of
Acute Asthma in
Primary and
Acute Care
Setting

PNAA 2016

NO HIGH DOSE ICS IS

USED IN THE PNAA
2016
PNAA; 2016.
 Management of
Acute Asthma in
Primary and
Acute Care
Setting

PNAA 2016

NO HIGH DOSE ICS IS

USED IN THE PNAA 2016

PNAA; 2016.
 Treatment in Acute Care Setting

O x y ge n Other :
- i p r a t ro p i u m
Inhaled short- b ro m i d e
acting-beta - a m i n o p hy l l i n e /
ago n i s t ( S A B A ) t h e o p hy l l i n e
- m ag n e s i u m ,
Systemic
- LT R A
c o r t i c o s t e ro i d
- ICS/LABA
(SCS)
• First-line and First step : Inhaled SABA
• Second-line therapy to incomplete response to
inhaled SABA : Systemic Corticosteroid
GINA; 2018.
 Overview
Corticosteroid in the Treatment
of Asthma
 Role of Corticosteroids in Treatment of Asthma

The most powerful anti-inflammatory drug→ inhibition of

production of inflammatory cytokines

The main role is to block the coding of inflammatory

genes on multiple targets (Classic/Genomic effects)

The first-line drug for asthma as a controller &

reliever

The most widely targeted anti-inflammatory drug

Rapid nongenomic effects on airway smooth muscle tone

& mucosal blood flow (rapid , transient, dose dependent)--
-rapid vasoconstrictor effect

Hossny. World Aller J. 2016;9(26):1–24.

 How about inhaled
corticosteroid (ICS) in
algorithm treatment of
acute asthma???
Cellular Effects of Corticosteroids in
Asthma Exacerbation

• Reduce the
inflammatory
ICS cells in
asthmatic
airways
 Hocchaus (1997) → ‘Airway selectivity’ Concept
→ Lung-related parameter (pulmonary deposition, pulmonary
residence time, pulmonary drug release) as important as
pharmacokinetics parameter (systemic clearance and oral
bioavailability)

Local disposition
Airway kinetics
Systemic disposition
Edsbacker S et al. Basic Clin Pharmacol Toxicol. 2006;98:523–36.
 Pharmacokinetic properties promoting safety and efficacy of inhaled corticosteroids. ↑,↓ =
corresponds to improved, reduced or no influence, respectively
Parameter Efficacy
Formulation Greater lung deposition with
optimal particle size
Prodrug structure Increased efficacy if pulmonary
retention is imporoves. Reduced
efficacy if intact prodrug is
systematically absorbed
Pulmonary High availability results in increased
availability lung exposure
Receptor affinity Increased anti-inflammatory activity
with strong receptor binding
Local esterification Longer pulmonary retention
prolong efficacy
Oral availability The orally available fraction will not
contribute to efficacy
Lipophilicity Increase lung retention and
duration of action but also
mucociliary clearance
Protein binding Conceptually only free drug is
associated with effect: therefore
efficacy should decrease with
increased protein binding
S)ystemic clearance No effect on pulmonary efficacy of
rapid clearance
Systemic half-life Prolongation of systemic hafl-life
unlikely to affect efficacy in the lung
Edsbacker S et al. Basic Clin Pharmacol Toxicol. 2006;98:523–36
Safety
Reduced incidence of local adverse events
when lung deposition is maximized
If prodrug completely activated, safety will
not be affected. Local safety will be improved
for prodrugs which are not activated in
oropharyngeal area
High availability increase systemic exposure
but reduce oral waist
Reduced receptor binding results in lowered
incidence of systematic adverse effect
Little influence if limited peripheral
esterification
If oral availability is significant, systemic
exposure and incidence of adverse effects will
increase
Increased systemic retention might increase
the risk of adverse events
(systemic effects associated with free drug
only)
Reduced potential for adverse effects with
rapid decrease
Lower systemic risk with reduced elimination
hal-life
Airway Selectivity
↑ with optimal particle size
↑ if pulmonary retention of active
metabolite is improved and/or
oropharyngeal activation is reduced
↓ for prodrugs which are systematically
absorbed
= for a drug with no or little oral
availability
↑ for an orally available drug molecule
=
↑ if greater local than systemic
esterification
↓
= or ↓ depending on relative degree of
lung and systematic retention
= (in the linear part of the dose-response
curve for efficacy and safety)
↑ with increased clearance
↑ with shorter half-life
 Pharmacokinetics and
Pharmacodynamics of ICS
Physical clearance mechanisms of the
mucocilliary escalator

Pulmonary Drug Dissolution

Pulmonary Absorption

Pulmonary Metabolism

Edsbacker S, et al. Basic & Clinical Pharmacology. 2006;98:523–36 INFERO 2019

 Pharmacokinetics of Inhaled
Corticosteroid

Barnes PJ. Pharmaceuticals. 2010:3;514–40.

 Airway
Corticosteroid exert effect on
vasculature
-- Mediated
Classic genomic
by rapid cellular
Controlling clinical symptoms of asthma
- mechanisms
Regulation primarily
of target gene
- Induce
Supresstransient
most of the
by influencing airway -caliber in the lung
vasoconstriction in of
vascular elements the airway
periphery and airway-hyperreactivity
inflammation
Reversing and
inflammatory
angiogenesis in airways
hyperfusion

Horvath G et al. Eur Respir J. 2006;27:172–87.

 Cellular Action of Corticosteroid
( Genomic and Non-Genomic Response)

Horvtah G et al. Eur Respir J. 2006; 27:172–87.

 Cellular Actions of Corticosteroid
(Genomic and Non-Genomic Response)
Mechanism of actions of inhaled corticosteroids in asthma
Genomic or classic anti-inflammatory Non-genomic
action
Action mediated Cytoplasmic glucocorticoid receptor Membrane-bound or cytoplasmic
through glucocorticoid receptor or direct interaction
with airway vasculature
Onset of action Hours to days Seconds to minutes (rapid onset, short
Peak induce vasoconstriction
duration-reversible, dose dependent)

Effects •
between• 30Suppressing
Selective switch off in multiple
and 60the min after drug
increased
inhalation microvascular permeability and plasma
activated inflammatory genes
(transrepression) by reversal of leakage into the airway lumen
histone acetylation • Acutely suppressing airway hyperfusion
• Increasing mRNA degradation and in a dose-dependent manner
hence blocking production of pro- • Inhibiting the remodeling process (only
inflammatory cytokines long-term therapy in a dose-dependent
• Increasing the synthesis of anti- manner)
inflammatory proteins

Edsbacker S. et al. Basic & Clinical Pharmacology. 2006;98:523–

Rodrigo GJ. Chest.2006;130:1301-11
 Inhaled GC: Inhibit airway mast cell degranulation
(allergic asthma model of guinea pig) within 10 min

→ Inhibit IgE-mediated exocytosis and

histamine release of mast cells
In vitro GC nongenomic effect
GC
→ nuclear receptor
mediated by ↓antagonist nor protein
[Ca2+] elevation
synthesis inhibitor could block the rapid
action

Zhou J et al. Allergy. 2008;63:1177–85.

Various Inhaled Corticosteroids

Pressurized Meter
Dose Inhaler Dry powder
(pMDI)

Nebulizer
 Inhaled Cor ticosteroid (ICS)

Nebulization

Jet
Budesonide Inhalation
Various Inhaled Corticosteroids

Fluticasone Beclomethasone
Furoate

Budesonide Mometasone
 FLUTICASONE PROPIONATE (FP)
• A potent dan poorly oral absorbed topically active
corticosteroid and extensively metabolized in the
liver to an inactive compound

• A highly lipophilic drug with high affinity to lung

GRs and has a slow rate of dissociation from its
receptor

• Readily absorbed through the respiratory mucosa

and can enter the systemic circulation

Carolyn M et al. Kendig’s Disorders of the Respiratory Tract in Children. Ninth Ed; 2019 pp 686-21.
 FLUTICASONE PROPIONATE (FP)
• More likely to produce sore throat and hoarseness
than other ICS

• Considered a high-potency ICS with the potential

to effectively control symptoms and improve lung
function

• But a higher doses it has greater potential to cause

adverse effects

Carolyn M et al. Kendig’s Disorders of the Respiratory Tract in Children. Ninth Ed; 2019 pp 686-21.
 BECLOMETHASONE (BDP)
• BDP is less potent than FP dan Budesonide (BUD)

• Effective in reducing symptoms and improving

pulmonary function

• BDP is readily absorbed from the gastrointestinal tract

and has a less favourable topical-to-systemic potency
ratio

• Concerns about its ability to cause adverse effects such

as growth and adrenal suppresion have not been
substantiated
Carolyn M et al. Kendig’s Disorders of the Respiratory Tract in Children. Ninth Ed; 2019 pp 686-21.
 MOMETASONE
• Mometasone is potent and highly topically active
steroid

• Advantage:
– Poor systemic absorption
– Effective in improving lung function and controlling
asthma

• Mometasone is similar to FP in its high receptor

affinity and half-life

• not available in Indonesia

Carolyn M et al. Kendig’s Disorders of the Respiratory Tract in Children. Ninth Ed; 2019 pp 686-21.
 BUDESONIDE (BUD)

• BUD had moderate potency (in vitro and in vivo) with

well-documented clinical efficacy and safety

• BUD molecule had a free C21 hydroxyl group, results in

formation of esters with long-chain fatty acids

• BUD formation, an inactive state remains in the

epithelial airways and release slowly into an active state

Carolyn M et al. Kendig’s Disorders of the Respiratory Tract in Children. Ninth Ed; 2019 pp 686-721.
Janson C. et al, Int J of Pulm, 2017;12: 3055–64.
 The reversible process of budesonide endogenous
esterification with fatty acids in the airway/lung tissue

Janson C et al. Int J Pulm. 2017;12;3055–64.

Jendbro et al. Am Soc Pharmac Exper Ther. 2001;29;769–76.
 BUD has a Faster Dissolution Rate than
FP and BDP
• After ICS is inhaled and deposited in the airways, it needs to be dissolved before
it can enter the airways and lung
• High water solubility increases the rate and extent of pulmonary uptake which in
turn improves intracellular accessibility and cytosolic receptor site
concentrations
• BUD is readily dissolved in human bronchial secretions and rapidly absorbed,
but fluticasone propionate, beclomethasone are more slowly dissolved.
Budesonide dissolves >50 times faster than BDP, and >80 times faster than FT

Edsbacker S et al. Basic Clin Pharmacol Toxicol 2006; 98(6):523–36.

 Molecular Structure Results in Rapid
Pharmacological Onset of Action

Edsbacker S et al. Basic Clin Pharmacol Toxicol 2006;98(6):523–36.

Pharmacological Properties of Budesonide and Fluticasone

ICS Budesonide Fluticasone

Mean Absorption 1 hour 7 hours
Time
Tmax 15.5 mins 50.8 mins
Half LIfe 2.8 hours and low 14.4 hours and high
systemic potency systemic potency
Water Solubility 16 <0.1
(ug/mL)
Dissolutions Time 6 mins >8 hours
Residence Time in Similar or longer Shorter
airway/lung tissue
Volume distribution Low (183 L) High (318 L)
Pneumonia risk Low High

Direkwattanachai et al. Asian Pac J Allergy Immunol. 2019. DOI 10.12932/AP-170918-0407.

 topical and retention of GCS in airway tissue
Comparison between inhaled GCS and noninhaled GCS [budesonide (BUD),
fluticasone propionate, beclomethasone dipropionate (BDP) >< dexamethasone,
hydrocortisone]
BUD form very lipophilic intracellular fatty acid ester
After 20 min of topical application, 70⎼80% was conjugated,
stored in esterified for prolonged time

Explanation for BUD is efficacious on treatment of

mild asthma when inhaled once daily

Miller-Larrshon A et al. Drug Metab Dispos. 1998;623–30.

 Airway retention time – BUD vs FT

The reversible conjugation BUD in airway may improve airway

selectivity as well as prolong the local anti-inflammatory action
of BUD in the airways might be one explanation for why BUD is
efficacious in the treatment of mild asthma when inhaled once
daily
Edsbacker S et al. Basic Clin Pharmacol Toxicol. 2006;98(6):523–36.
 Inhaled Corticosteroid (ICS)

Some studies have used high dose ICS (1600

mcg/day, preferably divided into four doses
over the day and given for 5–10 days)
2015 (Evidence D)
2018
→ reduce the need for oral corticosteroid
(OCS)
≤5 → adding nebulized budesonide to existing
ye a r treatment (including OCS) reduced length
of stay (Evidence D)

Razi et al. Int Arch Allergy Immunol. 2015;166(4):297–303.

Connett et al. Arch Dis Child. 1993;68:85–7.
 Inhaled Corticosteroid (ICS)
A d u l t , A d o l e s c e n t , 6 –1 1 y r s

E M G : high dose ICS given within 1

2015 hour after presentation → reduce need
2018 for hospitalization (Evidence A)

H o m e : reduces risk of asthma related

death/hospitalization (Evidence A), post-
discharge ICS were as effective as systemic
corticosteroids for milder exacerbations
(Evidence B)
Edmonds et al. Cochrane Database Syst Rev. 2012;1–113.
 Efficacy and Safety of
Efficacy and Safety
Budesonide of Budesonide in Asthma
in Asthma
Exacerbation in Children
Exacerbation (Studies Results)
in Children
(Studies Results)

Methods
RCT: 40 children (+- 10,7 yrs)
Objective: compare efficacy
of single dose of 2 mg vs 4
repeated doses 500 ug with
acute asthma exacerbation
Measurement: FEV1, asthma
score and oxygen saturatio
Razi et al. Ann Allergy Asthma Immunol. 2008;100:370–76.
Conclusion:
Use single dose nebulized budesonide
is as effective as repeated
administration of the same total
dosage during 1st 90 minutes
Results:
No significant difference in FEV1,
asthma scores, oxygen saturation
between 2 groups

Methods
RCT: Children 2-7 years,
Acute Asthma ( Asthma
Severity Score)
Objective: compare the
efficacy of single dose
nebulized budesonide (2 mg)
vs oral prednisone
Measurement: Asthma
Severity Score and
haemoglobin saturation
Milani et al. J Pediatr. 2004;80(2):106–12.
2004
Results
Prednisone group showed significant
hemoglobin saturation improvement
compared to their baseline at 2 hours
(p < 0.05)
Budesonide at 4 hours (p < 0.01).
• Single-dose nebulized budesonide
may be as effective as oral
prednisone
• Budesonide increases hemoglobin
saturation in exacerbation of
asthma
 Objectives
The efficacy of nebulized ICS in children
with moderate-to severe acute
Results
exacerbation of asthma
• Improvement in FEV1
• Complete remission rate
Methods
• Need for oral RCT
corticosteroids → Nebulized salbutamol and ipratropium bromide
significantly lower Addition of nebulized high-dose budesonide
(0.05% (2 mL) (BUD group, n = 60) vs normal
saline (control group,n = 58), three doses in the
first hour

Chen A. et al. Respirology. 2013;18:47–52.

 Method

0.5% Sabutamol 150g/kg

H-ICS
0.025% Iprotropine 250g
（n=59）
0.05% BIS 1mg(2ml) Inh. 3
5-15yr
M- times
exacer
within
bation
0.5% Sabutamol 150g/kg
Convention 1hr
0.025% Iprotropine1ml 250g
（n=54）
NS 2ml

Chen AH et al. Respirology. 2013;18(3)3:47–52.

 Change of FEV 1%

Chen AH et al. Respirology. 2013;18(3)3:47–52.

 Oral Corticosteroid (OCS) Use and Admission

Chen AH et al. Respirology. 2013;18(3)3:47–52.

 Study Recommendation

Add-on nebulized high-dose ICS can be

recommended to be used with nebulized short-
acting bronchodilators (salbutamol and ipratropium
bromide), three dosage in the first hour.

Nebulized high-dose ICS can be used as first-line

therapy of moderate to severe acute exacerbation
(non-life threatening) of childhood asthma

Chen AH et al. Respirology. 2013;18(3)3:47–52.

 2014

Results
Methods
RCT
• Severe Acute Asthma Group;
Nebulized Budesonide (BUD) (1500 BUD had 58% reduction in
μg) vs Placebo (Normal Saline) the risk of hospital
Children aged 2-12 tahun, Moderate admission
or Severe Acute Asthma Exacerbation • Asthma Severity Score
Outcome: Hospital admission rate and
Asthma Severity Score
significantly lower in BUD
group

Alangari et al. Chest. 2014;145:772–8.

 2015

Methods
- Single-center, double-blind, Results
placebo-controlled and parallel ▪ Total hospital LOS:
group trial significantly shorter in
- Children aged 7-72 months, BUD group
asthma exacerbation (Clinical ▪ Reduce the overall cost of
Asthma Score) 3-9
treatment
- Treatment group: addition of
inhaled Budesonide 2 mg/day (n:
50) vs control group: Inhaled NS 2
mL (n:50)
Razi et al. Int Arch Allergy Immunol. 2015;166(4):297–303.
 Total hospital LOS was Discharge rates were
significantly shorter in the significantly higher in the
budesonide group than the budesonide group at 48, 60
placebo group and 72 h

Razi et al. Int Arch Allergy Immunol. 2015;166(4):297–303.

 Effects of High Dose Budesonide on Admission

Results

Total hospital LOS was significantly shorter 45% in

budesonide group vs. placebo (median 44 vs 80h)

Nebulized budesonide reduce the overall

p = 0.01 cost of
treatment

LOS (hour)
Razi et al. Pediatric Pulmonology. 2017.52:720–728.
Saito et al. Eur Ann Allergy Clin Immunol. 2017;49(1):22–27.
 Efficacy and Safety of High-dose
Budesonide vs Systemic Corticosteroid in
Mild Exacerbations (<3yr)
Baseline characteristics and treatment
Nebulised Budesonide (BIS) group Sistemic Corticosteroid group
Parameters
(n = 30) (n = 20)
Age (months) 20 ± 2 21 ± 2
Gender (M/F) 21:9 15:5

Body weight (kg) 81 ± 1 83 ± 2

Height (cm) 11 ± 0 12 ± 0

Hospitalised patients (children < 3 years) with bronchial asthmaa

experiencing mild asthma exacerbation were randomized to:
Nebulised BUD (BIS) group Systemic steroid therapy (PSL) group
1 mg of nebulized BUD bid 0.5 mg/kg prednisolone Q8h, iv

Saito et al. Eur Ann Allergy Clin Immunol. 2017;49:22–27.

 Wheezing High-dose nebulized
disappeared after budesonide therapy
an average of five was at least not
days in both inferior to systemic
group steroid therapy

Hospitalized patients (children < 3 years) with bronchial asthma experiencing

mild asthma exacerbation were randomized to:

Nebulized BUD (BIS) group Systemic steroid therapy (PSL) group

1 mg of nebulized BUD bid 0,5 mg/kg prednisolone Q8h, iv

Saito et al. Eur Ann Allergy Clin Immunol. 2017;49(1):22–27.

 Budesonide has Equivalent or Improved Clinical
Outcomes Compared with Systemic Corticosteroid
Both groups Budesonide group
Wheezing disappeared after a Serum cortisol suppression did
mean of 5 days
not occur in patients treated
Steroids were administered for a with BUD (BIS), suggesting high-
mean of 5 days
No significant difference in days dose nebulized BUD for ~5 days
of oxygen use is unlikely to have systemic
effects
Clinical outcomes BIS group (n=30) PSL group (n=20)
Days of wheezing detected 5±0 5±1
Days of steroid therapy 5±0 5±0
Patients with desaturation 8 6
Days of oxygen required 2±1 3±1
Serum cortisol at admission (μg/dL) 15.0 ± 2.2 17.2 ± 2.1
10.9 ± 1.5
Serum cortisol at re-examination 17.0 ± 1.2
(P = 0.0036)
Days after admission for re-examination 4±0 4±0

Saito et al. Eur Ann Allergy Clin Immunol. 2017;49(1):22–27.

 • Recommendation
• Nebulized high-dose corticosteroid is recommended in
13theRCT (1998-2017):
treatment 200 patients
of all severities 1-18
of asthma yrs, 3
exacerbation
times
(mild,daily budesonide
moderate, and severe)800 mcg- 3 mg
•→ It Nebulized
may be usedbudesonide
within the first hour of presentation
without suppressionof
acute treatment
• ofNebulized
pituitarybudesonide
adrenal axisis the preferred corticosteroid

Thailand
Management of Pediatric Asthma Exacerbation in Hospital
Direkwattanachai et al. Asian Pac J Allergy Immunol. 2019. DOI 10.12932/AP-170918-0407.
 Studi Pendukung Rekomendasi Terapi Nebulisasi pada
Tatalaksana Eksaserbasi Asma Anak
Asthma
Author Treatment arms Results
Severity
Saito, 2017 Mild 1. Neb BUD 1 mg BID + SoC BUD and PSL similar efficacy.
2. 3x/d IV PSL 0. mg/kg + SoC Serum cortisol unchanged with
BUD, decreased with PSL (safety)
Yanagida, 2015 Moderate 1. Neb 0,01% procaterol Lower frequency of inhalations
hydrochloride + 1% DSCG and IV mPSL on days 3-6 of hospitalization
1mg/kg, 3x/d with BUD.
2. Neb 0,01% procaterol Signif. higher cortisol level at
hydrochloride + BUD 0,5mg, 3x/d discharge with BUD.
Razi, 2015 Moderate- 1. SoC3 + 2mg/d neb BUD for up to Signif. shorter LOS with neb BUD.
severe 5 day Signif. less inpatients with neb
2. SoC3 + Pbo for up to 5d BUD.
Neb BUD reduced the overall
cost of treatment.
Alangari, 2014 Addition of neb BUD signif.
Moderate- 1. 3x/20’ nebBUD 0,5mg + SoC2 decrease in admission rate and
severe 2. 3x/20’ Pbo + SoC2 signif. greater drop in asthma
score in severe AEA.
Chen, 2013 Signif. improvement FEV1 at 1
1. 3x Neb sol 0,5% Salb + 0,025% IB
and 2h with BUD.
Moderate- (1mL) + 0,05% BUD (2mL)
Signif. higher complete
severe 2. 3x Neb sol 0,5% Salb + 0,025% IB
remission rate and signif. lower
(1mL) + Pbo (2mL)
need for oral CS with BUD.
Rapid Effects on Inhaled Corticosteroids in Acute
Asthma
An Evidence-Based Evaluation
• Published RCT (1996-2006) from different data bases-adults & children
• Primary outcome: admission and ED discharge rates

CONCLUSION
❑ ICS present early beneficial effects (1 to 2 h) when used in multiple
doses administered in time interval < 30 min over 90 to 120 min.
❑ A possible candidate: NON GENOMIC EFFECT

IMPLICATIONS FOR PRACTICE

Due to variation between studies, the evidence suggest
nebulized budesonide doses: 800 μg every 30 min
nebulized fluticasone 500 μg every 15 min
The doses have to be administered during minimum 90 min

Rodrigo CJ. Chest. 2006;130:1301-11

• Various Inhaled Corticosteroids has different properties:
• Budesonide has a Faster Dissolution Rate than
Fluticasone Propionate (FP) and Beclometasone
dipropionate (BDP)
• Budesonide has Rapid Pharmacological Onset of Action vs
FP and BDP
• Budesonide has equivalent or Improved Clinical Outcomes
Compared with Systemic Corticosteroid without decreasing
cortisol level in children with mild acute exacerbation
• Add on budesonide in standard treatment for hospitalized
children with acute asthma reducing 45% lengths of stay (LoS)
Results of Advisory Board Meeting of Respirology
Coordination Working Unit - !6 December 2019

“Nebulization Treatment in Children with Acute Asthma”

 Hasil Pertemuan UKK Respirologi mengenai Terapi
Nebulisasi pada Tatalaksana Eksaserbasi Asma Anak

Jenis Serangan Rekomendasi Terapi

• SABA + SCS atau SABA + ICS dosis tinggi
Budesonide nebulisasi sebagai terapi alternatif/ pengganti kortikosteroid
Ringan - Sedang
sistemik
Dosis 1-2 mg setiap nebulisasi dengan frekuensi 2x/hari
Penambahan budesonid nebulisasi 1 mg dalam 2 ml sebanyak 2x sehari dapat
Berat
menurunkan lama perawatan di rumah sakit

Informasi Tambahan

• Kortikosteroid inhalasi lebih aman dibandingkan kortikosteroid sistemik

• Budesonid yang dipakai untuk serangan asma harus sediaan 0.5 mg/mL atau 1
mg/respule sediaan 2 mL
• Frekuensi pemberian: di rumah 1 x; di IGD diberikan bersamaan dengan SABA
• Kortikosteroid nebulisasi direkomendasikan diberikan sampai 3-5 hari
• Kortikosteroid nebulisasi tidak boleh diberikan dengan ultrasonic nebulizer
THANK YOU