The New Role of Nebulized Steroid

for Acute Asthma in children

Darmawan B Setyanto
Indonesian Pediatric Society
Respirology WG

May 7, 2019
Darmawan B Setyanto, MD
Born: 11 April 1961

Education:
◼ Medical Doctor, Faculty of Medicine, University of Indonesia, 1986
◼ Pediatrician, Faculty of Medicine, University of Indonesia, 1997
◼ Respirology Consultant, 2005

Current position :
◼ Head of Respirology Division, Dept of Child Health, Faculty of Medicine,
University of Indonesia

Organization:
◼ Member of MKEK (Majelis Kehormatan Etik Kedokteran Indonesia)
◼ Chairman of Respirology Coordination Working Unit, Indonesian
Pediatric Society 2008-2014
◼ IPS: Member of C Board, CPD committee, Paediatrica Indonesiana, IPS
Bulletin
◼ APSR, ERS, EAACI member
Aerosol therapy in children
common pitfalls

Darmawan B Setyanto
Indonesian Pediatrics Society
List of nebulization pitfalls
◼ Indication
o Nebulization for upper airway symptoms
o Steroid inhalation as reliever for acute airway symptoms
o ‘Package system’
◼ Device
o ...
◼ Drug
o Nebulized non-nebulization drug (injection drug, oral drug)
o ‘Routine’ mix drug combination: -agonist, steroid,
mucolytic – underdose each
◼ Do NOT ‘diluting’ the drug
 Asthma pathogenesis
cough, dyspnea
symptom wheezing, …

Airway
pathophys Triggers: smoke, obstruction
dust, HDM, ...

Airway Inflammation oedema, Broncho-

pathology remodelling Th2, mast c, eos hypersecretion spasm

Enhancers: indoor AHR

adaptive allergen,mold,... Immune response: Autonomic
response Th2, IgE, IgG4, IgG1 imbalance
Inducers: ozone
rhinovirus, ... AHR:
Genetically airway hyper-
Insult susceptible responsiveness
 Asthma: chronic - acute
attack
attack
symptom
symptom

MPI
Asthma
time
MPI:
Chronic
minimal asthma: how frequent the symptom –
persistent attack appear during certain time
inflammation
Acute asthma: how severe the symptom –
inflammation attack that appear at a point time
 Acute asthma

failure of long-term exposure to strong

asthma treatment or multiple triggers

Progressive worsening of symptoms

i.e. cough, dyspnea, wheezing, chest tightness,
or combination of those symptoms
 Spectrum of acute asthma, clinical
Life threatening attack

Severe attack

Moderate attack

Mild attack

Symptoms

NO symptoms
Steps of asthma treatment

1. Avoidance of trigger(s)

2. Avoidance of trigger(s)

3. Avoidance of trigger(s)

a. Reliever
4. Drug(s)
b. Controller
Asthma medication

Reliever • To relieve acute asthma

drug • As needed medication
• If the symptom-attack relieve, stop
(pereda)

• To control asthma inflammation

Controller • Long term medication, months - years
drug • Evaluated regularly,
• Dose adjusment: maintain, step-up,
(pengendali) step-down
 Asthma treatment, step 4a
cough, dyspnea
symptom wheezing, …
Reliever
Airway
pathophys Triggers: smoke, obstruction
dust, HDM, ...

Airway Inflammation oedema, Broncho-

pathology remodelling Th2, mast c, eos hypersecretion spasm

Enhancers: indoor AHR

adaptive allergen,mold,... Immune response: Autonomic
response Th2, IgE, IgG4, IgG1 imbalance
Inducers: ozone
rhinovirus, ...
Genetically
Insult susceptible
Autonomic nervous system
 Asthma treatment, step 4a
cough, dyspnea
symptom wheezing, …
Reliever
Airway
pathophys Triggers: smoke, obstruction
dust, HDM, ...

Airway Inflammation oedema, Broncho-

pathology remodelling Th2, mast c, eos hypersecretion spasm

Enhancers: indoor AHR

adaptive allergen,mold,... Immune response: Autonomic
response Th2, IgE, IgG4, IgG1 imbalance
Inducers: ozone
rhinovirus, ...
Genetically
Insult susceptible
Acute asthma treatment in PHC facility
Acute asthma reliever drug
Topical, Inhalation: Nebulizer or MDI+spacer
◼ Reliever inhalation drug:
o β2 agonist: salbutamol, terbutaline, fenoterol,
procaterol
o Anti-cholinergic: ipratropium bromide
o β2 agonist + anti-cholinergic
◼ Inhaled steroid ???
Systemic: enteral, parenteral
◼ Systemic steroid (oral, injection)
◼ Xanthin: aminophylline, theophylline
◼ Magnesium sulfate (MgSO4)
 2020

Mild-moderate Severe
•Short acting -agonist • SABA
(SABA)
• Anti-cholinergic
•[Consider anti-
cholinergic] • Controlled O2
•Controlled O2 • Oral steroid
•Oral steroid • Consider IV MgSO4
Children <5y • Consider high dose
Mild-moderate, Severe Acute Asthma ICS
Prednisolone 2 mg/kg BW
Systemic steroid
Important in the treatment of severe acute
asthma
◼ Speed resolution
◼ Prevent the progression
◼ Reduced hospitalization
◼ Prevent early relaps
◼ Reduce the morbidity of illness

GINA 2012-2020
Asthma medication

Reliever • To relieve acute asthma

drug • As needed medication
• If the symptom-attack relieve, stop
(pereda)

• To control asthma inflammation

Controller • Long term medication, months - years
drug • Evaluated regularly,
• Dose adjusment: maintain, step-up,
(pengendali) step-down
 Inhaled CS for reliever ?
◼ ICS: budesonide (Pulmicort® respule) and fluticasone
(Flixotide® nebule) – to control chronic inflammation
◼ It is designed as controller, NOT as reliever
◼ Steroid as reliever – systemic administration (oral OR
injection)
Systemic effect?
◼ ICS as reliever – a very common (mis)practice
Anti-acute
o Based on concept: wrong!
inflammation?
o Evidence based medicine??? – high dose!!!
OR
Other mechanism?
o High cost!
◼ Not recommended as routine management
Advisory Board Meeting
The role of budesonide-formoterol and
budesonide in children with asthma

Sunday, 30 Sep 2018

JS Luwansa Hotel Jakarta
Enlighted!
Indonesian Pediatric Society
Respirology Working Group
Inhalation therapy
Naso-
pharyngeal
airway
AIRWAY
Airflow
Larynx
Conducting
zone
Tracheo-
bronchial
tree
Neb adrenalin for CROUP
as a vasoconstrictor
Respiratory Zone

Diffusion
 2006

Arch Bronconeumol. 2006;42(10):533-40

Introduction
◼ Husby et al, 1993
◼ important landmark
◼ RCT
◼ children
◼ severe croup
◼ single dose of 2 mg of neb budesonide or a placebo,
◼ rapid clinical improvement (within 2 hours)
Mechanism
◼ Hyperemia and hyper-perfusion are consistent features
of inflammation.
◼ Asthma, therefore, is expected to be associated with an
increased airway blood flow
Eur Respir J 2006; 27: 172–187

◼ Classic effect of c-steroid by affecting the transcription

of gene (genomic effect)
◼ it has been demonstrated that the c-steroids have
biological effects that are independent of the gene
transcription process which is called as non-genomic
effect
◼ produce a much faster response, within seconds or
minutes
Arch Bronconeumol. 2006;42(10):533-40
 2006

ABSTRACT: ICS suppress airway inflammation and components of

airway remodelling in bronchial asthma. In the tracheobronchial
(airway) vasculature, these include the inhibition of inflammatory
hyperperfusion, microvascular hyperpermeability, mucosal oedema
formation, and the formation of new blood vessels (angiogenesis).

In this review article, recent advances into the understanding of

cellular mechanisms and the clinical implications of the interaction of
inhaled corticosteroids and the airway vasculature in asthma are
reviewed.
Mechanism
◼ Corticosteroids are now known to exert their effects
on the airway vasculature through genomic and non-
genomic mechanisms.
◼ Genomic actions involve the regulation of target
genes, and suppress most of the vascular elements of
inflammation and angiogenesis in the airway.
◼ In contrast, non-genomic actions are mediated by rapid
cellular mechanisms, and induce vasoconstriction in
the airway, thereby reversing inflammatory hyper-
perfusion.
◼ The vascular actions of corticosteroids contribute to
controlling clinical symptoms of acute asthma
Eur Respir J 2006; 27: 172–187
Mechanism Arch Bronconeumol. 2006;42(10):533-40

Anti-inflammatory Vasoconstrictor
effect (classic) effect (NEW)
Mechanism Eur Respir J 2006; 27: 172–187
Mechanism

Transient effect of inhaled fluticasone on airway mucosal blood flow in subjects with and without asthma.
Am J Respir Crit Care Med 2000;161:918–921.
 Asthma treatment, step 4a
cough, dyspnea Reliever
symptom wheezing, …

Airway
pathophys Triggers: smoke, obstruction
dust, HDM, ...

Airway Inflammation oedema, Broncho-

pathology remodelling Th2, mast c, eos hypersecretion spasm

Enhancers: indoor AHR

adaptive allergen,mold,... Immune response: Autonomic
response Th2, IgE, IgG4, IgG1 imbalance
Inducers: ozone
rhinovirus, ... AHR:
Genetically airway hyper-
Insult susceptible responsiveness
Early publ of neb steroid for acute asthma
◼ Pansegrouw DF. Acute resistant asthma caused by excessive beta-2
agonist inhalation and reversed by inhalation of beclomethasone. S
Afr Med J. 1992;82:179-82.
◼ Scarfone RJ, Loiselle JM, Wiley JF, Decker JM, Henretig FM, Joffe
MG. Nebulized dexamethasone versus oral prednisone in the
emergency department of asthmatic children. Ann Emerg Med.
1995;26:480-6.
◼ Edmonds ML, Camargo CA Jr, Pollack CV Jr, Rowe BH. Early use of
inhaled corticosteroids in the emergency department treatment of
acute asthma. The Cochrane Database of Systematic Review; 2003.
Issue 3. 10.1002/14651858.
◼ Foresi A, Paggiaro P. Inhaled corticosteroids and leukotriene
modifiers in the acute treatment of asthma exacerbations. Curr
Opin Pulm Med. 2003;9:52-6.
◼ Hendeles L, Sherman J. Are inhaled corticosteroids effective for
acute exacerbations of asthma in children? J Pediatr. 2003;142:S26-
S33.
Arch Bronconeumol. 2006;42(10):533-40
 2006

◼ Objective: The analysis of the best evidence available on

the early (1 to 4 h) clinical impact of ICS for patients with
acute asthma in the ED setting.
◼ Methods: Published (1966 - 2006), RCT, were retrieved
using different databases (MEDLINE, EMBASE,
Cochrane Controlled Trials Register), bibliographic
reviews of primary research, review articles, and
citations from texts. Primary outcome measures were
admission and ED discharge rates.
Pooled OR for hospital admissions

The overall weighted OR showed a significantly

lower admission rate in patients treated with ICS
Pooled OR for discharge rate

Significant greater proportion of ICS-treated patients

were discharged from the ED compared with either
placebo or with SCS
 2015

Background:
We investigated whether budesonide inhalation suspension (BIS)
could replace IV steroid for the treatment of moderate acute
asthma.

Subjects & Methods:

• RCT
• Children <5y, hospitalized, moderate acute asthma.
• 2 groups: 20 patients methylprednisolone (mPSL) and 20
patients budesonide (BIS).
• The cortisol level at discharge was measured.
 2015

Results:
• No significant differences: severity of attacks, duration of
management, therapeutic efficacy, duration of wheezing,
period of hospitalization.
• the frequency of inhalations on days 3-6 of hospitalization was
lower in the BIS group
• the cortisol level at discharge: BIS group (13.9 ± 6.1 μg/dL);
mPSL group (8.0 ± 2.1 μg/dL) --- (p = 0.008).

Conclusion:
• the efficacy of BIS  > mPSL
• BIS treatment do not suppress adrenocortical function.
 2015

Objective: to investigate whether the addition of high-

dose inhaled budesonide to standard therapy would
shorten the length of stay (LOS) in hospital of children
admitted for acute asthma
Methods:
• Single-center, double-blind, placebo-controlled and
parallel-group trial.
• Children aged 7–72 months
• Clinical asthma score (CAS) between 3 - 9 were
allocated to either the budesonide (n = 50) or the
placebo (n = 50) group.
Results:
• The number of inpatients was significantly less in the
budesonide group at all the assessed end points
(Kaplan-Meier; p = 0.022).
• Total hospital LOS was significantly shorter in the
budesonide group (median: 44 vs. 80 h, respectively;
p = 0.01).
• Nebulized budesonide was found to reduce the
overall cost of treatment.
 2015

Conclusion:
Children hospitalized for acute asthma, an additional
2 mg/day of nebulized budesonide significantly
reduced hospital LOS as well as the overall cost of
treatment.
 Neb BUD for acute asthma in children studies

Author, jrnal, Acute asthma Poso-

Treatment arms Outcomes
year, size, age severity logy

1. 3x/30’ neb Salb 0.15mg/kg and 0.8mg/

BUD sig.: improved SaO2, resp rate,
Devidayal, 1999 Pbo + 1x oral PSL 2mg/kg 30’
Moderate-severe pulm index, resp distress score and
n=80 (2-12 yrs), 2. 3x/30’ neb Salb 0.15mg/kg and 2.4mg
increased patients fit for discharge.
BUD 0,8mg + 1x Pbo total

1. 2x/6h nebTerb 0, mg/kg 0.05mg Neb BUD, but not Terb, rapidly
Tsai, JPed, 2001 2. nebTerb 0,1mg/kg and neb BUD /kg decreased eNO.
Moderate
n=30 (6-17 yrs), (0,05mg/kg; max 2mg) + nebTerb 2 mg The decrease in eNO levels
0,1mg/kg after 6h max correlated to an increase in PEFR.
1. Greater reduction in admission
rate after 2–4 hours of
Rodrigo, Chest,
1. ICS + SABA (vs. placebo) treatment
2006, meta Moderate-severe
2. ICS + SABA (vs. placebo or SCS) 2. Faster clinical improvement,
increasing probability of early
ED discharge
Signif. improvement FEV1 at 1 and
Chen, Respi, 1. 3x Neb sol 0,5% Salb + 0,025% IB 1mg/2
2h with BUD.
(1mL) + 0,05% BUD (2mL) 0’
2013, n=118, Moderate-severe
2. 3x Neb sol 0,5% Salb + 0,025% IB 3 mg
Signif. higher complete remission
(6-10 yrs) rate and signif. lower need for oral
(1mL) + Pbo (2mL) total
CS with BUD.
 Neb BUD for acute asthma in children studies
Acute
Author, jrnal, Poso-
asthma Treatment arms Outcomes
year, size, age logy
severity

Alangari, Chest, 0.5mg/ Addition of neb BUD signif.

Moderate- 1. 3x/20’ neb BUD 0,5mg + SoC2 20’ decrease in admission rate and
2014, n=906 2. 3x/20’ Pbo + SoC2 1,5mg signif. greater drop in asthma score
severe
(2-12 yr) total in severe AEA.

1. Neb 0,01% procaterol

hydrochloride + 1% DSCG and IV mPSL  frequency of inhalations on BUD.
Yanagida, WAO,
Moderate 1mg/kg, 3x/d Signif. higher cortisol level at
2015, (≤ 5 yr) 2. Neb 0,01% procaterol discharge with BUD.
hydrochloride + BUD 0,5mg, 3x/d

Razi, IAAI, 2015, Signif. shorter LOS with neb BUD.

1. SoC3 + 2mg/d neb BUD for up to 5
Moderate- Signif. less inpatients with neb BUD.
n=100, (7-72 severe
day 2mg/d
Neb BUD reduced the overall cost
mo) 2. SoC3 + Pbo for up to 5d
of treatment.

Saito, EAACI, 1mg

BUD and PSL similar efficacy.
1. Neb BUD 1mg BID + SoC 2x/d,
2017, n=50 Mild
2. 3x/d IV PSL 0. mg/kg + SoC Total 2
Serum cortisol unchanged with
(<3 yr) BUD, decreased with PSL (safety)
mg
 2019

Objective: To review and recommend the practical

considerations in the use of nebulized corticosteroid in
children with acute asthma.
Methods:
• Thailand expert pediatricians in respiratory & allergy
• Review of published studies & clinical opinions
• English, RCT & meta-analyses
• Nebulized CS in acute asthma, children 1-18 years.
 2019

Results:
• 13 RCT studies from 1998 - 2017.
• 9 nebulized >< systemic CS; moderate to severe
• 4 nebulized CS >< placebo; mild to severe
• The admission rate was significantly lower in severe
exacerbation (one study) and pooled four mild to
severe exacerbation studies comparing with placebo
(p 0.022).
• Other clinical parameters were significantly improved
with nebulized CS such as clinical scores, systemic CS /
SABA use, or shorter ER stays.
• 1 study fluticasone, 12 studies budesonide.
 2019

Conclusion:
• Nebulized CS may offer an effective
therapeutic option for the management of
acute asthma in all severities.
• Nebulized budesonide is the preferred
corticosteroid.
Advisory Board Meeting II
The role of budesonide-formoterol and
budesonide in children with asthma

Sunday, 16 Des 2018

JS Luwansa Hotel Jakarta

Indonesian Pediatric Society

Respirology Working Group
1st launching in
PITIKA Manado
2019
Asma serangan ringan-sedang
Rekomendasi 1
• Pasien yang mengalami serangan asma ringan-sedang diberikan
inhalasi β2 agonist kerja pendek (short-acting β2 agonist/ SABA).
• Untuk anak di atas 5 tahun, selain β2 agonist juga diberikan
kortikosteroid sistemik ATAU kortikosteroid inhalasi dosis tinggi
sebagai pereda.
• Untuk anak balita, jika menunjukkan perbaikan klinis setelah terapi
dengan inhalasi SABA, kortikosteroid tidak perlu diberikan.
Rekomendasi 2
• Pemberian obat pereda inhalasi menggunakan pMDI+spacer sama
efektifnya dengan pemberian melalui nebuliser.
• Kortikosteroid ampul harus diberikan dengan nebuliser jet, tidak
boleh dengan nebuliser ultrasonik.
• Cara inhalasi dengan DPI tidak sebaik nebuliser atau pMDI+spacer.
Asma serangan berat
Rekomendasi 3
• Pasien anak asma yang mengalami serangan asma berat, diberi
inhalasi kombinasi SABA dan antikolinergik ditambah dengan
kortikosteroid sistemik intravena sebagai pereda.
• Jika setelah terapi tidak ada perbaikan, maka selanjutnya
DITAMBAH dengan kortikosteroid inhalasi dosis tinggi.
Asma dengan ancaman henti napas
Rekomendasi 4
• Pasien anak asma yang mengalami serangan asma berat dengan
ancaman henti napas, lakukan inhalasi kombinasi SABA dan
antikolinergik DITAMBAH dengan kortikosteroid sistemik
intravena DAN kortikosteroid inhalasi dosis tinggi yang keduanya
diberikan sebagai obat pereda.
Rekomendasi 5
• Terapi inhalasi pada asma serangan berat dan ancaman henti napas
diberikan dengan menggunakan nebuliser.
Take home messages
◼ Nebulized c-steroid (NCS) can be used for acute
asthma in children as a reliever
◼ Not anti-inflammatory, but vasoconstrictor effect
modality
◼ It gives a very fast response (seconds-minutes)
◼ Should be given in a high dose
◼ Among NCS, budesonide has a large body of
evidence
◼ Ad-interim recommendation: nebulization of BUD
1 mg, twice a day, 5 days
April 2012 | Volume 7 | Issue 4 | e35797
Abstract
…
• Procedures reported to present an increased risk of transmission
included [n; pooled OR(95%CI)] tracheal intubation [n = 4 cohort;
6.6 (2.3, 18.9), and n = 4 case-control; 6.6 (4.1, 10.6)], NIV [n = 2
cohort; OR 3.1(1.4, 6.8)], tracheotomy [n = 1 case-control; 4.2 (1.5,
11.5)] and manual ventilation before intubation [n = 1 cohort; OR
2.8 (1.3, 6.4)].
• Other intubation associated procedures, endotracheal aspiration,
suction of body fluids, bronchoscopy, nebulizer treatment,
administration of O2, high flow O2, manipulation of O2 mask or
BiPAP mask, defibrillation, chest compressions, insertion of
nasogastric tube, and collection of sputum were not significant.
• Our findings suggest that some procedures potentially capable of
generating aerosols have been associated with increased risk of
SARS transmission to HCWs or were a risk factor for transmission,
with the most consistent association across multiple studies
identified with tracheal intubation.
Global Initiative for Asthma (GINA)
What’s new in GINA 2020?

GINA Global Strategy for Asthma

Management and Prevention

© Global Initiative for Asthma

 COVID-19 and asthma (as at March 30, 2020)
◼ Avoid spirometry in patients with confirmed/suspected
COVID-19
o Spirometry can disseminate viral particles and expose staff and
patients to risk of infection
o While community transmission of the virus is occurring in your
region, postpone spirometry and peak flow measurement within
health care facilities unless there is an urgent need
o Follow contact and droplet precautions
◼ Follow strict infection control procedures if aerosol-
generating procedures (AGP) are needed
o For example: nebulization, oxygen therapy (including with nasal
prongs), sputum induction, manual ventilation, non-invasive
ventilation and intubation
o World Health Organization (WHO) infection control
recommendations are found here: www.who.int/publications-
detail/infection-prevention-and-control-during-health-care-when-
novel-coronavirus-(ncov)-infection-is-suspected-20200125
 COVID-19 and asthma (as at April 3, 2020)
◼ Advise patients with asthma to continue taking their
prescribed asthma medications, particularly inhaled
corticosteroids (ICS), and oral corticosteroids (OCS) if
prescribed
o Asthma medications should be continued as usual.
Stopping ICS often leads to potentially dangerous
worsening of asthma
o For patients with severe asthma: continue biologic
therapy, and do not suddenly stop OCS if prescribed
◼ Avoid nebulizers where possible
o Nebulizers increase the risk of disseminating virus to other
patients AND to health care professionals
o Pressurized metered dose inhaler via a spacer is the
preferred treatment during severe exacerbations, with a
mouthpiece or tightly fitting face mask if required
 Canada
Nebulizer is to be used only in the following situations:
▪ Patients with severe, life-threatening respiratory
disease (e.g., those with severe or impending
respiratory arrest, or those with hypoventilation or
ventilation compromise, continuous nebulization,
end-stage chronic obstructive pulmonary disease,
cystic fibrosis); or
▪ Patients who are uncooperative or are unable to
follow the directions required for using a metered-
dose inhaler with spacer; or
▪ Patients with a history of poor response to metered-
dose inhaler with spacer.
CMAJ 2020 March 30;192:E346. doi: 10.1503/cmaj.75066
 Nebulizers and Infection Transmission Risk
o If patient can tolerate, switch to MDI with a spacer.
o HCWs should use PP: a facemask, as eye protection, gloves
and a gown during treatment if a respirator is unavailable.
o Close patient’s door when providing nebulizer treatment.
o Upon set-up of nebulizer, have HCWs maintain a safe
distance (6 feet or greater), possibly outside the door.
o Patients do not need to be transferred to a higher level of
care solely for the purpose of providing nebulizer
treatment.
Minnesota Department of Health
www.health.state.mn.us
Tell patients, or their parent or carer, they can
continue to use their nebuliser. This is because
the aerosol comes from the fluid in the
nebuliser chamber and will not carry virus
particles from the patient.
Presented at:
◼ Webinar
◼ Dep IKA FKUI-RSCM
◼ Jakarta
◼ Sun, 03 May 2020