The Use of Inhaled Corticosteroids in the Treatment of Asthma is Children in the Emergency Room
Condition: Status Asthmaticus
MeSH terms: Status Asthmaticus; Emergencies
Study type: Interventional
Phase: Phase 2/Phase 3

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): Budesonide; Normal saline
Intervention type(s): Drug; Drug
Intervention description(s): 500 mcg budesonide plus Albuterol plus ipratropium bromide (IB) nebulization, 3 doses back to back; 0.5 ml to 1.5 ml normal saline (to complete 3 mls total volume), plus albuterol plus ipratropium bromide nebulizations 3 doses back to back
Other intervention name(s): Pulmicort
Intervention MeSH terms: Budesonide
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary purpose: Treatment