Prednisolone in acute asthma in children

Paediatric asthma

Prof Colin F Robertson

Respiratory Medicine,

Royal Children’s Hospital, Melbourne.

Respiratory Medicine, RCH, Melbourne.

Topics

natural history

patterns of asthma

treatment

is it asthma?


Hospital admissions – Australia 1993-2007

Outcome of childhood asthma


0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

Control MWB WB A SA

PA

FA

IA

NRA

Outcome of childhood asthma at 50 years


0%

20%

40%

60%

80%

100%

14 21 28 35 42 50

Age

No Remission

Remission

0%

20%

40%

60%

80%

100%

14 21 28 35 42 50

Age

No Remission

Remission

0%

20%

40%

60%

80%

100%

14 21 28 35 42 50

Age

No Remission

Remission

Asthma remission

Mild and wheezy bronchitis

Asthma

Severe asthma

Remission

No remission


FEV1 outcome over time at age 50


Lung function over time - classification: those who remained within the same severity groups at each review

70

80

90

100

110

10 14 21 28 35 42

FE

V1

% P

red

icte

d

age at review (years)

Controls

NRA / IA

FA / PA

Patterns of asthma


Pattern of asthma

Intermittent asthma

isolated episodes

attacks – mild to severe

symptoms rare in between attacks

normal examination and lung function

between attacks

often seasonal (winter months)


Pattern of asthma

Persistent asthma

symptoms between attacks

sleep disturbance > 1 night/week

exercise induced wheeze / limitation

use of beta2 agonists > 3 times per week

abnormal lung function between attacks


Patterns of asthma in children

intermittent ~ 75-85%

persistent ~ 10-15%


Paediatric hospital admissions for asthma

Intermittent 87%

Persistent 13%

Ordonnez, Arch Dis Child 1998


Paediatric emergency department attendances for asthma

Intermittent 89%

Persistent 11%

Khan MS, J Paediatr Child Health. 2003


Paediatric general practitioner attendances for asthma

intermittent

infrequent 76%

frequent 20%

persistent 4%

Khan MS, J Paediatr Child Health. 2003

Intermittent asthma

Viral associated wheeze

Viral infection in wheezing exacerbations in children

viruses identified in up to 85% of wheezing exacerbations, in children:

Rhinovirus, Coronavirus, Influenza virus, Parainfluenza virus, Respiratory syncytial virus (RSV)

seasonal correlations between rates of upper respiratory tract infections (URTIs) and hospital admissions for asthma

Johnston SL BMJ 1995 Pattemore PK et al. Clin Exp Allergy 1992


Intermittent asthma - therapeutic options

inhaled β – agonists

oral corticosteroids

oral montelukast


Inhaled β – agonists

pMDI and spacer

children under 6 years 2-6 puffs

children over 6 years 2-12 puffs

frequency – up to 2 hourly as needed


Initial salbutamol 10 puffs or neb 2.5/5.0mg

Baseline assessment PRAM (within 5 mins)

Prednisolone or placebo

<24 months 10mg 12/12 11kg, 24/12 13kg

>24 months 20mg 36/12 15kg, 60/12 19kg

Given daily for 5 days

Oral prednisolone for preschool children with acute virus-induced wheezing

Grigg NEJM 2009


Oral prednisolone for preschool children with acute virus-induced wheezing

700 children 10 months to 5years

Attend Emergency Department

Viral associated wheeze (clinical Dx)

Exclusions:

Shock, sepsis

Heart disease

Previous non-asthma lung disease

Immunodeficient / immunosuppressed

Grigg NEJM 2009

Primary outcome

Grigg NEJM 2009

Primary outcome: duration of admission

Interval between presentation and signoff for discharge

Median (hour) 12.0 10.1 -1.9 (-6.5 to 4.1)

http://content.nejm.org.ezp.lib.unimelb.edu.au/content/vol360/issue4/images/large/06f2.jpeg


Oral corticosteroids

Preschool children No evidence of benefit

Reserve for in hospital use

School age children Modest benefit

Reserve for more severe episode



prednisolone

– 2mg/kg first dose

then 1mg/kg daily for up to 3 days


1) Inhaled short-acting β2-agonists on an as-needed basis should be used for the symptomatic treatment of acute wheezing in preschool children. These drugs should be used cautiously in infants since paradoxical responses have been reported in this age group.

2) Alternative routes of administration (oral / iv) should not be used.

3) Addition of ipratropium bromide to short-acting β2-agonists may be considered in patients with severe wheeze.

ERS recommendations: Acute wheezing episode Pre-school


4) A trial of oral corticosteroids should probably be given to preschool children with acute wheeze of such severity that they need to be admitted to hospital.

5) Parent-initiated treatment with a short course of oral corticosteroids should not be given.

6) Although high-dose ICS therapy appears to have a small beneficial effect in the treatment of acute wheezing, this treatment is not recommended because of high cost and lack of comparison to bronchodilator therapy.

ERS recommendations: Acute wheezing episode Pre-school


Oral montelukast – in intermittent asthma

intermittent use, commenced at the beginning of an episode

25% reduction in health resource utilization

37% reduction in days off school

35% reduction in parent time lost from work

Persistent asthma


Increase ICS

FP or BDP 250mcg/day CIC 160 ug/day

BUD 500-800mcg/day

Further increase dose of ICS to max:

FP or BDP-HFA 500mcg/day CIC 320 ug/day

BUD 800mcg/day

+?? long-acting beta2 agonist

Oral leukotriene

antagonist

(montelukast)

Low dose inhaled corticosteroids

FP or BDP 100-200 ug/day CIC 80 ug/day

BUD 200-400 ug/day

Check:

diagnosis

technique

adherence

Remember:

back titration

Approach to preventative therapy in children


Dose - response curve for inhaled corticosteroids

90% max

0 50 100 200 400 600 800 1000

Daily dose of inhaled steroid (FP ug)

Cli

nic

al

eff

ect

Clinical Benefit

Adverse effect

Differential diagnosis – pre-school years

bronchiolitis

recurrent post infective cough

cystic fibrosis

aspiration - 10 or 20

cardiac failure

structural abnormalities

foreign body

Recurrent non-specific (post viral) cough

common in pre-school children

paroxysmal cough - asymptomatic between paroxysms

night > day

with exercise

triggered by urti

duration 2-4 weeks

not associated with wheeze

not responsive to asthma therapy

Differential diagnosis – pre-school years

bronchiolitis

transient infant wheeze

recurrent post infective cough

cystic fibrosis


cardiac failure


foreign body

Investigation

Investigations

Good clinical history – the cornerstone

wheeze – often difficult to be precise

noisy breathing that responds to bronchodilator

Examination

often normal

look for features to suggest other diagnoses

Investigations

Chest x-ray

only indicated if unusual history, wheeze unresponsive to treatment or severe persistent wheeze

Bronchoscopy

as for above

bronchial biopsy abnormal – not helpful

Microbiology

virus common

academic interest

Investigations

Allergens skin prick test to aeroallergens

32% bd responsive v 11% healthy

more likely to wheeze beyond six years

not helpful clinically

IgE not helpful clinically

Lung fucntion research only

Investigations

In general, other investigations should probably not be carried out unless wheeze is unusually severe, therapy-resistant or accompanied by unusual clinical features

Transient infant wheeze

approx 2/3 of recurrent infant wheezing

reduced lung function in infancy

no associated atopy

no family history of atopic disease

maternal smoking major risk factor

poor response to asthma therapy

resolves spontaneously by 2-3 years

Persistent wheeze

approx 1/3 of recurrent infant wheezing

normal lung function in infancy

associated atopy - eczema

family history of atopic disease

Good response to asthma therapy

continues beyond 2-3 years

Inhaled β2 – agonists

long acting inhaled β2 – agonists

no evidence of benefit in preschool children

Inhaled β – agonists

pMDI and spacer

children under 6 years 2-6 puffs

frequency – up to 2 hourly as needed


Parent-initiated oral corticosteroids not effective in

preschool aged children

ERJ, 2008

Parent-initiated oral corticosteroids not effective in

preschool aged children

Primary outcome

Grigg NEJM 2009

Prednisolone in preschool children

http://content.nejm.org.ezp.lib.unimelb.edu.au/content/vol360/issue4/images/large/06f2.jpeg

To evaluate the efficacy of parent-initiated

prednisolone in school aged in the management of

exacerbations of asthma

Parent-Initiated Prednisolone in Asthma A Randomised Controlled Trial

Design

Community based study

Children aged 5 to 12 years

Diagnosis of asthma established by a paediatrician

4 or more episodes in preceding year

Double blind, randomised, placebo controlled, cross-

over trial

episodes were randomised rather than participants

Recruitment

Survey of asthma

symptoms among

primary school students

Identified population

derived sample of

children for RCT

Intervention

Episodes of acute asthma were defined by the following advice given to parents:

“If from previous experience you suspect this is a more severe attack, or if the symptoms are not getting better in about 6 to 8 hours with regular use of reliever medication, give your child the study medication immediately.”

Prednisolone 1mg/kg daily for 3-5 days

Consented: n = 230

Withdrew: n=2

Lost to follow-up: n=3

No episodes: n=69

Prednisolone: n = 155

132 participants, 308 episodes

Placebo: n = 153

3 y

ears

Baseline characteristics

Age 7.9 (2.1) years

Male 69%

Interval symptoms 43%

Asthma preventive 69%

Atopic sensitisation 72%

Eczema 58%

Results

Prednisolone

(n=155)

Placebo

(n=153)

Difference

(95% CI)

p value

Daytime symptom

score (mean, SD)

4.1 (2.8) 4.6 (2.5) ↓15% (26% to 2%)

0.023

Night time

symptoms score

0.6 (0.6) 0.7 (0.6) ↓16% (0% to 30%)

0.05

Results

Prednisolone

(n=155)

Placebo

(n=153)

Odds ratio

(95% CI)

NENT

(95% CI)

p Value

Health

resource

utilisation

31% 45% 0.55

(0.34 to 0.87) 7.1

(4.0 to 30.3)

0.011

Hospital

admission 4% 8% 0.41

(0.16 to 1.05) 25

(10.7 to )

0.064

Medication

substituted 19% 35% 0.44

(0.26 to 0.74)

6.2

(3.9 to 16.1)

0.002

Conclusions

Among primary school aged children with asthma parent-initiated prednisolone is associated with a modest reduction in:

Asthma symptoms

Health resource utilisation

but….

Consider the risk benefit ratio

Cochrane review

Placebo admission rate > 40%

Pred 2mg/kg or 30mg<5, 60mg >5, Methylpred 2or4mg/kg


Parent initiated OCS (~1mg/kg) ineffective in pre-school children

Emergency dept OCS (~1mg/kg) ineffective in pre-school children

Cochrane review in older children effective in dose of 2mg/kg prednisolone

Recommended for episode severe enough to require admission to hospital 2mg/kg initial dose, 1mg/kgtherafter

Oral montelukast

Intermittent use, commenced at the beginning of an episode

reduces symptoms

reduces health resource utilisation

Approach to preventative therapy

IFWIN Study

Infants less than 3 years

1 prolonged or 2 short episodes of wheeze

Fluticasone 100ug bid or placebo

Followed to 5 years

Murray, Lancet 2006

IFWIN Study – outcome at 5 years

Placebo Fluticasone

FEV1

(L/s)

1.04 (0.96,1.12)

1.03 (0.96,1.10)

FEV1 post bd (L/s)

1.06 (0.96,1.16)

1.05 (0.96,1.14)

sRAW (kPa/s)

1.28 (1.17,1.40)

1.32 (1.22,1.43)

sRAW post bd (kPa/s)

1.02 (0.95,1.09)

1.05 (0.98,1.12)

Murray, Lancet 2006

Peak Study – inclusion criteria

Children aged 2-3 years at high risk for asthma with: A history of 4 or more wheezing episodes with at least one

physician diagnosed and at least one of the following major conditions or at least 2

of the following minor conditions

Major Criteria Parental history of asthma MD-diagnosed atopic dermatitis Allergic sensitization to at least one aeroallergen

Minor Criteria Allergic sensitization to milk,egg, or peanuts Wheezing unrelated to colds Blood eosinophils above 4%

Guilbert, NEJM 2006

PEAK study

recruited at 2-3 years

at high risk of developing asthma continuing through childhood

randomised to FP 100ug bd or placebo for 2 years

drug then stopped and child followed for a further year

Guilbert, NEJM 2006

Other medications

xanthines

cromones

antihistamines

Cochrane reviews little evidence of benefit in pre-school children

Summary

Acute wheeze

inhaled - agonist administered via spacer and facemask – the treatment of choice

oral steroids – trial if severe enough to require admission to hospital

Parent initiated steroids should not be given

inhaled cholinergics only in severe episode

Intermittent LTRAs at onset may reduce symptoms

Summary

Maintenance treatment

achieves control – not effect natural history

lTRA v ICS

intermittent agonists

poor response

think about diagnosis, adherence

think abut referral

Difficult asthma

Difficultlt asthma

The European Respiratory Society defines difficult asthma in children as asthma that is not controlled despite treatment with >800 ug budesonide or equivalent for adults – 400ug for children

Difficult asthma

1. the diagnosis is wrong (“not asthma at all”), and a diagnostic re-evaluation is essential;

2. the asthma is mild, but exacerbated by one or more comorbidities (“asthma plus”);

3. whether this is “difficult-to-treat asthma” because of potentially reversible factors such as poor adherence to treatment or poor inhalation technique;

4. they have true “severe, therapy-resistant asthma”, which remains refractory to treatment even when reversible factors have been taken into account

the diagnosis is wrong -not asthma at all

< 2 – 3 years

bronchiolitis

transient infant wheeze

cystic fibrosis


cardiac failure


foreign body

the diagnosis is wrong -not asthma at all > 2 – 3 years

recurrent post-infective cough

poor cardiopulmonary fitness

hyperventilation / anxiety

protracted bronchitis

chronic suppurative lung disease

exercise induced stridor

irreversible airflow obstruction

gastro-oesophageal reflux

hysteria


Detailed history

medical

psychosocial

Lung function

spirometry and bronchodilator response

bronchial challenge

Allergy testing

useful for specific allergens – pets


Radiology

chest x-ray

HRCT – with expiratory view

bronchiectasis, obliterative bronchiolitis

Bronchoscopy

if suspected

structural abnormality

suppurative lung disease

the asthma is mild, but exacerbated by one or more comorbidities

gastro-oesophageal reflux

rhinosinusitis

dysfunctional breathing

obesity

food allergy

environmental allergy

pertussis

difficult-to-treat asthma –

poor adherence to treatment

< 50% pick up > 80% prescribed Rx

~ 30% pick up < 50% prescribed Rx

poor inhalation technique

poor training - may be hard to correct

psychosocial factors

anxiety and depression

true “severe, therapy-resistant asthma”

no accepted definition of steroid resistance

no response in symptoms or lung function after 2 weeks of oral prednisolone

true congenital steroid resistance is rare

trial i.m. triamcinolone

omalizumab, methotrxate, cyclosporin, Azothioprine

Case 1

8 year old boy referred for assessment of persistent cough and reduced exercise tolerance

no response to high dose LABA and ICS

Case 1

associated eczema

family history of asthma

marked exercise intolerance

mild pectus carinatum

Case 1 – lung function

FEV1 0.61L or 35%P No bronchodilator response

Management

oral steroids

review – no better – refused to take

i.m. triamcinolone

Case 1 – lung function (2)

FEV1 0.82L or 42%P

Post bronchodilator

FEV1 1.2L or 68%P

Case 1 – lung function (3)

FEV1 1.5L or 84%P

Post bronchodilator

FEV1 1.7L or 98%P

Case 2 – exercise induced dyspnoea

common presentation , particularly in adolescents

often EID attributed to asthma

Lab study

45% presenting with EID – no EIB

following exercise, rate of symptom recovery similar between EIB+ and EIB-

Case 2 – exercise induced dyspnoea

Management of EIB

pre treat with inhaled agonist

inhaled corticosteroids

montelukast

long acting agonists

warm up

Alternative diagnoses

poor cardipulmomary fitness

obesity

exercise induced laryngeal dysfunction syndrome

vocal cord dysfunction

structural abnormalities tracheomalacia

traceal stenosis

interstitial lung disease

Case 4

12 year old with Down syndrome

long standing exercise intolerance

biphasic wheeze/stridor

unresponsive to bronchodilators

Tracheal stenosis

Asthma mortality

Asthma mortality in Australia 1979-2005

Asthma mortality, Australia 1920-2000 5-34 year olds

0

0.5

1

1.5

2

2.5

1920

1925

1930

1935

1940

1945

1950

1955

1960

1965

1970

1975

1980

1985

1990

1995

2000

Ra

te p

er

10

0,0

00

po

p

Risk factors

•33% trivial or mild asthma

•32% no previous hospital admission for asthma

•36% severe asthma

•22% previous admission to ICU

•63% sudden onset and collapse within minutes

•ICU admission requiring ventilation

5% mortality within 10 years

Preventable factors

Of 20/51 death with preventable factors

Inadequate assessment or therapy of previous asthma - 68%

•Poor compliance with seemingly appropriate therapy - 53%

•Delay in seeking professional help – 47%

•Delay in receiving medical help - 21%

•Geographic isolation - 11%

Management of acute asthma

Treatment Mild episode Moderate episode Severe and life-threatening episode

Hospital admission necessary Probably not Probably Yes: consider intensive care

Supplementary oxygen Probably not required May be required. Monitor SaO2 Required. Monitor SaO2. Arterial blood gases may

be required.

Salbutamol1* 4-6 puffs (under 6 years) or

8-12 puffs (6 years and

over). Review in 20 mins

6 puffs (under 6 years) or 12 puffs (6

years and over).

If initial response inadequate, repeat at

20-minute intervals for two further doses.

Then give every 1-4 hours.

6 puffs (under 6 years) or 12 puffs (6 years and

over) every 20 mins for three doses in first hour.

If life-threatening episode, use continuous

nebulised salbutamol.

If no response, bolus IV salbutamol 15 mcg/kg over

10 mins then 1 mcg/kg/min thereafter.

Ipratropium14 Not necessary Optional 2 puffs (under 6 years) or 4 puffs (6 years and over)

every 20 minutes x 3 doses in first hour

or nebulised ipratropium

Systemic corticosteroids Yes (consider) Oral prednisolone

1 mg/kg daily for up to 3 days

Oral prednisolone

2 mg/kg/ initial dose then 1mg/kg daily for up to 5

days

Methylprednisolone IV 1 mg/kg 6 hourly on Day 1,

12 hourly on Day 2 then daily

Magnesium11 No No Magnesium sulphate 50% 0.1 ml/kg (50 mg/kg) IV

over 20 mins then 0.06 ml/kg/hr (30 mg/kg/hr):

target serum Mg 1.5-2.5 mmol/L

Aminophylline15 No No Only in Intensive Care: loading dose 10 mg/kg

Maintenance 1.1 mg/kg/hour if under 9 years or 0.7

mg/kg/hour if 9 years and over

Chest X-ray Not necessary unless focal

signs present

Not necessary unless focal signs present Necessary if no response to initial therapy or

pneumothorax is suspected

Observations Observe for 20 mins after

dose

Observe for 1 hour

after last dose

Arrange for admission to hospital

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Prednisolone in acute asthma in children