The Use of Inhaled Corticosteroids in the Treatment of Asthma is Children in the Emergency Room
The Use of Inhaled Corticosteroids in the Treatment of Asthma is Children in the Emergency Room
Asthma is the most common chronic illness of childhood. About 10% of children are affected.
 Not surprisingly, acute asthma exacerbations are one of the common reasons to visit pediatric
 emergency rooms (ER). About 5.7% of all pediatric emergency room visits are due to acute
 asthma exacerbation. Around 8% of those get admitted to the hospital. This constitutes huge
 financial and administrative burden on the health care system.

 Inhaled corticosteroids (ICS) is the gold standard prophylactic therapy for patients with
 persistent asthma. In the setting of acute asthma exacerbation systemic steroids given early
 in the course of treatment help decrease the rate of admission and return to the ER. However,
 the anti-inflammatory action of corticosteroids, through which this effect is caused, takes 4
 hours to start working. This is because it is mediated through genomic pathways where the
 transcription of several inflammatory cytokines is suppressed. It was also shown that
 corticosteroids can cause vasoconstriction through non-genomic pathways. The onset of this
 action is as quick as 30-60 minutes. It is proposed that this action is mediated by blocking
 the extraneuronal uptake (metabolism) of norepinephrine in vascular smooth muscle cells,
 hence, making it available for re-use by the sympathetic neuronal cells.

 Our objective is to compare the efficacy of adding repetitive sequential doses of budesonide
 versus placebo (normal saline (NS)) to β2-agonist and ipratropium bromide (IB) combination
 (standard treatment) in the management of acute asthma in children in the ER. We hypothesize
 that the addition of budesonide to β2-agonist and IB in the management of moderate to severe
 acute asthma in the ER is superior to the addition of placebo.
Asthma is the most common chronic disease of childhood and the most common cause of admission
 of children to the hospital. Children in Saudi Arabia have a relatively high prevalence of
 asthma compared to many other countries for reasons that are not clear. The prevalence has
 increased during the past 20 years2 following, and sometimes exceeding, the same pattern
 noted in Western countries one decade ago. As stated earlier about 5.7% of all ER asthma
 visits are because of asthma exacerbation and about 8% of those children gets admitted to the
 hospital.

 Corticosteroids (CS) can show two different effects on acute asthma patients:

 1. The classic anti-inflammatory or genomic action implicates the activation or repression
 of multiple genes involved in the inflammatory process. Thus, CS produce their effects
 on cells by activating glucocorticoid receptors that alter transcription through direct
 DNA binding. In addition, ligand activated glucocorticoid receptor (GR) can bind
 pro-inflammatory transcription factors like NFkB (Nuclear Factor kappa B) or activating
 protein-1 leading to their inactivation. Consequently, CS increase the synthesis of
 anti-inflammatory proteins, or inhibit the synthesis of many inflammatory proteins
 through activation or suppression of the genes that encode them. Moreover, CS has been
 shown to block the production of several pro-inflammatory cytokines by increasing their
 mRNA (messenger ribonucleic acid) degradation rate. These effects occur with a time lag
 of about 4-24 hours. So far all the recommended uses of CS in asthma therapy are related
 to this mode of action, including the use of systemic CS in patients with asthma
 exacerbation in the emergency room.

 2. The nongenomic action, which has a rapid onset (minutes), is reversible (short duration
 of 60-90 minutes), and is dose dependent. A protective effect was demonstrated 2 hours
 after a single dose of 100 mcg of fluticasone propionate inhaler using bronchial
 provocation with cyclic adenosine monophosphate (cAMP). Higher doses were reported to
 cause more significant effects. Asthmatics present a significant increase in airway
 mucosal blood flow in comparison with healthy subjects. Calculated as in the volume of
 the conducting airways from the trachea to the terminal bronchioles, mean airway blood
 flow values were 24-77% higher in asthmatics than in healthy controls. The inhalation of
 fluticasone (880 mcg) or budesonide (400 mcg) significantly decreases blood flow in both
 groups, but more in asthmatics. Evidence suggests that CS decrease airway blood flow by
 modulating sympathetic control of vascular tone. CS inhibit the extra-neuronal monoamine
 transporter- mediated uptake of norepinephrine by bronchial arterial smooth muscle
 cells, therefore, potentiating noradrenergic neurotransmission in the airway
 vasculature. This action is possibly mediated by binding of CS to membrane bound GR in
 smooth muscle cells of human airway blood vessels. This effect is a topical local one
 and is a feature of Inhaled CS (ICS) rather that systemic CS (SCS). Furthermore, this
 decrease in airway blood flow is likely to enhance the action of inhaled bronchodilators
 by diminishing their clearance from the airway. Thus, simultaneous administration of ICS
 and bronchodilators could be of clinical significance. Accordingly, ICS would have to be
 administered simultaneously with bronchodilators in high and repeated or sequential
 doses as a way to obtain and maintain the effect throughout the time. Since ICS induced
 vasoconstriction peaks between 30 and 60 min after drug administration, their use in
 intervals not more that 30 min seems adequate.

 A recent meta-analysis comparing ICS with SCS; or ICS and SCS combination to placebo and SCS
 combination in the Emergency Room (ER), included 17 different randomized double blind placebo
 controlled trials with data for 1,133 subjects (470 adults and 663 children) were available
 for analysis. It concluded that ICS presents early beneficial effects (within 1 to 2 h) in
 terms of clinical and spirometric variables when used in 3 or more doses administered in time
 intervals ≤ 30 min over 90 to 120 min. ICS lead to a significant reduction in admission rate
 at 2 to 4 hours with only 10 subjects needed to be treated to prevent one admission. The
 nongenomic effect was suggested as a possible candidate by covering the link between
 molecular pathways and the clinical effects of CS. However, this issue remains controversial
 and the current asthma guidelines published by the National Heart, Lung, and Blood Institute
 (NHLBI) in the USA do not include the use of inhaled glucocorticoids in the treatment of
 asthma in the ER, while the Global Initiative for Asthma (GINA) guidelines suggested that it
 can be effective. This subject clearly needs to be studied further.

 The addition of inhaled anti-cholinergics (Ipratropium Bromide (IB)) to β2-agonists in the
 treatment of asthma in the ER was shown to be effective, especially in severe asthma, and is
 now considered a standard therapy. However, very limited data exist in comparing the addition
 of ICS to anti-cholinergics and β2-agonists combination in adults. In one study the use of
 triple therapy was superior to the combination of β2-agonist with either IB or ICS. Up to our
 knowledge, this issue was not previously investigated in children. Moreover, the protocols
 used for adults may not be practical for the use in children.

 Exhaled NO is a marker of airway inflammation. Its level is increased in several conditions
 of chronic airway inflammation. It correlates well with sputum eosinophilia and bronchial
 hyper-reactivity in none steroid treated subjects. It is useful as an adjunct in asthma
 diagnosis, monitoring asthma control, adherence to ICS, and in predicting asthma
 exacerbations. Its usefulness in the assessment of the severity of asthma exacerbations and
 response to treatment in the emergency room has not been determined yet. Few studies have
 shown that the measurement of Fractional Exhaled Nitric Oxide (FeNO) in the emergency room
 did not correlate with asthma severity or predict treatment outcomes. It also did not
 correlate with other measurements like symptom score or PEFR (peak expiratory flow rate).
 However, those studies were not in the same setting as we are proposing here. In other words,
 they were using standard medications only. Nevertheless, this issue needs to be studied
 further, especially with the evidence that ligand binding of the cytoplasmic GR leads to
 rapid activation of the NO synthase in endothelial cells and thereby may alter the level of
 FeNO. This study is a good opportunity to examine the value of measuring FeNO in the
 emergency especially that its measurement is easy, reliable and reproducible. The
 availability of new portable, valid, and reliable devices to measure FeNO (NIOX Mino) makes
 it even more attractive.

 Up to our knowledge, the design we are proposing here has not been studied before.

 Our objective is to compare the efficacy of adding repetitive sequential doses of budesonide
 versus placebo (normal saline (NS)) to β2-agonist and ipratropium bromide (IB) combination
 (standard treatment) in the management of acute asthma in children in the ER. We hypothesize
 that the addition of Budesonide to β2-agonist and IB in the management of moderate to severe
 acute asthma in the ER is superior to the addition of placebo.
Inclusion Criteria:

 -  Children 2-12 years of age with physician diagnosed asthma or a previous episode of
 SOB that responded well to β2-agonists who present to the ER with moderate or severe
 asthma exacerbation

 Exclusion Criteria:

 -  Children with mild asthma exacerbation.

 -  Children with severe asthma exacerbation who are in critical condition or need
 immediate intervention.

 -  Children who have heart disease or chronic lung disease other than asthma.

 -  Systemic steroids administered within the past 7 days.