Asthma Management Handbook

Guide to other asthma medicines

Overview

In addition to relievers and preventers, some other agents are occasionally used to manage asthma in specific circumstances, e.g. as add-on options for management of severe refractory asthma or severe acute asthma. They include:

  • anti-IgE (omalizumab)
  • anti-IL5 (mepolizumab) and anti-IL5 receptor (benralizumab)
  • long-acting muscarinic antagonists; also called long-acting anticholinergic bronchodilators (tiotropium via mist inhaler)
  • magnesium sulfate
  • theophyllines (aminophylline, theophylline).

Some additional long-acting bronchodilator medications are TGA-approved only for management of COPD, but might be used in addition to inhaled corticosteroid-containing therapy for the treatment of patients with asthma–COPD overlap. These include:

  • long-acting muscarinic antagonists; also called long-acting anticholinergic bronchodilators (aclidinium, glycopyrronium, tiotropium via dry-powder inhaler, umeclidinium)
  • long-acting beta2 agonists (e.g. vilanterol in combination with inhaled corticosteroid or long-acting muscarinic antagonist).

Note: The use of separate inhalers for concomitant treatment with an inhaled corticosteroid and a long-acting bronchodilator (long-acting beta2-agonist or long-acting muscarinic antagonist) in patients with asthma–COPD overlap should be avoided due to the risk of selective non-adherence with the inhaled corticosteroid. If no combination product is available for the desired combination, carefully explain to the patient that it is very important that they continue taking the inhaled corticosteroid, to reduce the risk of hospitalisation or death. 

Table. Classification of asthma medicines Opens in a new window Please view and print this figure separately: http://www.asthmahandbook.org.au/table/show/79

Table. Long-acting bronchodilators for asthma–COPD overlap

Class

Dosing frequency

Agent

Brand name

ICS–LABA combinations

Once daily

Fluticasone furoate + vilanterol

Breo Ellipta 100/25 microg

  • Do not prescribe 200/25 microg formulation#
Twice daily

Budesonide + formoterol

Symbicort Rapihaler

Symbicort Turbuhaler

Twice daily

Fluticasone propionate + formoterol

Flutiform

Twice daily

Fluticasone propionate + salmeterol

Fluticasone and Salmeterol Cipla

Seretide Accuhaler

Seretide MDI

LABAs*

Once daily

Indacaterol

Onbrez Breezhaler

Twice daily Formoterol

Oxis

Foradile

Twice daily Salmeterol

Serevent Accuhaler

LAMAs* Once daily Glycopyrronium

Seebri Breezhaler

Once daily

Tiotropium

Spiriva

Spiriva Respimat

Once daily

Umeclidinium

Incruse Ellipta

Twice daily Aclidinium

Bretaris Genuair

LABA–LAMA combinations*

Once daily

Indacaterol + glycopyrronium

Ultibro Breezhaler

Once daily

Olodaterol + tiotropium

Spiolto Respimat

Once daily

Vilanterol + umeclidinium

Anoro Ellipta

Twice daily

Formoterol + aclidinium

Brimica Genuair

  • * Ensure that patient is also using regular long-term ICS. LABAs and LAMAs should not be used by people with asthma or asthma–COPD overlap unless they are also taking an ICS, in combination or separately)
  • Advise patients/carers that inhalers should be stored below 30°C and should not be left in cars.

The inhaler must be discarded 1 month after opening the package and removing device from tray. When first opened, patients should write the discard date on the label in the space provided. If stored in the refrigerator, inhaler should be taken out and allowed to return to room temperature for at least an hour before use.

The inhaler must be discarded 6 weeks after opening the package and removing device from tray. When first opened, patients should write the discard date on the label in the space provided. If stored in the refrigerator, inhaler should be taken out and allowed to return to room temperature for at least an hour before use.

# Only the 100/25 microg dose of fluticasone furoate/vilanterol is TGA-approved for treatment of COPD. The higher dose (200/25 microg) is not TGA-approved for the treatment of COPD, so it should not be used in people with asthma–COPD overlap.

High doses of ICS (alone or in combination) are not recommended in patients with COPD and should therefore be used with caution in patients with asthma-COPD overlap, because of the risk of pneumonia.

Refer to PBS status before prescribing.

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More information

Ipratropium for children

Cochrane systematic reviews concluded that, overall, clinical trial evidence does not support the regular use of muscarinic antagonists (anticholinergic bronchodilators) in the maintenance treatment of asthma in children (i.e. outside the context of acute asthma).1

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Ipratropium for adults

Regular ipratropium bromide in addition to as-needed short-acting beta2 agonist does not appear to provide clinically significant benefit over as-needed short-acting beta2 agonists alone.2

Note: Ipratropium bromide may be used in the management of severe acute asthma.

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Tiotropium for children aged 6 years and over

Tiotropium (5 microg administered via mist inhaler as two puffs once daily) is approved by TGA for use in children aged 6 years and older with moderate-to-severe asthma.

Tiotropium is subsidised by then PBS for children aged 6–17 years when used in combination with maintenance ICS+LABA treatment, for patients with severe asthma treated by, or in consultation with, a specialist (respiratory physician, paediatric respiratory physician, clinical immunologist, allergist, paediatrician or general physician experienced in severe asthma management), with frequent moderate exacerbations or ≥ one documented severe exacerbation that required systemic corticosteroids in the previous 12 months despite maintenance treatment with a medium-to-high dose of inhaled corticosteroid in combination with a long-acting beta2 agonist, and correct inhaler technique has been assessed, demonstrated and documented (see PBS for details).

Children aged 6–11

A systematic review of three randomised controlled trials reported that, in children aged 6–11 years with moderate-to-severe symptomatic asthma, tiotropium improved lung function, improved symptoms, and reduced the rate of flare-ups.3 Tiotropium was generally well tolerated.3

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Tiotropium for adults and adolescents

Tiotropium via mist inhaler (not dry-powder inhaler) is approved by the TGA for add-on maintenance treatment in patients with moderate-to-severe asthma.4

Tiotropium is well tolerated.5, 6

Note: PBS status as at March 2019:

Adults: Tiotropium is subsidised by the PBS for use in combination with a maintenance combination of an inhaled corticosteroid and a long acting beta2 agonist for patients with severe asthma who have had at least one severe flare-up in the previous 12 months that required documented systemic corticosteroids, while receiving optimised asthma therapy with a combination of at least 800 mg budesonide per day or equivalent and a long acting beta2 agonist, and correct inhaler technique has been assessed, demonstrated and documented.

Children and adolescents aged 6–17 years: Tiotropium is subsidised by the PBS for use in combination with a maintenance combination of an inhaled corticosteroid and a long acting beta2 agonist for patients with severe asthma who have had at least one severe flare-up in the previous 12 months that required documented systemic corticosteroids, while receiving optimised asthma therapy with a combination of a medium-to-high dose of an inhaled corticosteroid and a long acting beta2 agonist, and correct inhaler technique has been assessed, demonstrated and documented.

Adults

Tiotropium added to inhaled corticosteroid therapy

A Cochrane review and meta-analysis that included five double-blind, double-dummy trials found that the addition of tiotropium to inhaled corticosteroid therapy reduced the risk of flare-ups requiring systemic corticosteroids and improved lung function, compared with the same dose of inhaled corticosteroid, in adults not taking a long-acting beta2 agonist.7

Another systematic review and meta-analysis of long-acting muscarinic antagonists (tiotropium or umeclidinium) in patients with poorly controlled asthma despite taking inhaled corticosteroids reported that the addition of a long-acting muscarinic antagonist significantly reduced the risk of an asthma flare-up requiring systemic corticosteroids, or of asthma worsening, compared with placebo.8 There were no significant effects on asthma control, reliever use or quality of life.8 In most included studies participants were adults with a mean age between 30 and 40 years.8

However, there is insufficient evidence overall to support the use of tiotropium as an alternative to a long-acting beta2 agonist as add-on therapy. In contrast, there is a large evidence base supporting the combination of inhaled corticosteroid and long-acting beta2 agonist in adults.

Tiotropium versus long-acting beta2 agonist added to inhaled corticosteroids

Few studies have compared tiotropium with long-acting beta2 agonists as add-on therapy in patients taking inhaled corticosteroids. Direct evidence is mainly limited to studies of less than 6 months’ duration comparing tiotropium with salmeterol. Meta-analysis of these studies showed no significant difference between treatment groups in flare-ups requiring oral corticosteroids, lung function, symptom control or asthma-related quality of life.8

While there is insufficient evidence to support the use of tiotropium as an alternative to a long-acting beta2 agonist as add-on therapy in patients taking an inhaled corticosteroid, it may be a suitable alternative for patients who have experienced adverse effects of long-acting beta2 agonist therapy.

Tiotropium added to the combination of inhaled corticosteroid and long-acting beta2 agonist

The addition of tiotropium bromide via mist inhaler therapy is effective in improving lung function and reducing worsening asthma in adults and adolescents with asthma that is uncontrolled despite taking a combination of inhaled corticosteroid and long-acting beta2 agonist, but does not reduce the rate of severe flare-ups requiring oral corticosteroid.8

A Cochrane review9 concluded that tiotropium in addition to the combination of an inhaled corticosteroid and a long-acting beta2 agonist may have additional benefits over inhaled corticosteroid/long-acting beta2 agonist alone in reducing the need for oral corticosteroids in adults with severe asthma.

Another systematic review and meta-analysis found that the addition of a long-acting muscarinic antagonist (tiotropium or umeclidinium) to the combination an inhaled corticosteroid and a long-acting beta2 agonist in adults significantly reduced the rate of worsening asthma, but not the rate of severe flare-ups requiring oral corticosteroids, and had no significant effect on other outcomes including lung function or symptom control.8

Adolescents

Tiotropium added to inhaled corticosteroid therapy

A meta-analysis of randomised placebo-controlled clinical trials in adolescents with asthma found that tiotropium as an add-on in patients taking inhaled corticosteroids improved lung function, reduced the rate of flare-ups, and improved asthma symptom control.6 In those with poorly controlled asthma despite treatment with medium-to-high doses of inhaled corticosteroids, tiotropium was not inferior to salmeterol.6

Another systematic review and meta-analysis of clinical trials of long-acting muscarinic antagonists in patients with poorly controlled asthma included only two trials evaluating tiotropium in adolescents aged 12–17 years. Tiotropium added to inhaled corticosteroid treatment was associated with numerical improvements in lung function, but this reached significance in comparison with placebo in only one study. Both studies in adolescents reported large placebo effects, which may have been due to improved adherence to inhaled corticosteroids during the trial.8

Tiotropium added to the combination of inhaled corticosteroid and long-acting beta2 agonist

A meta-analysis of randomised placebo-controlled clinical trials in adolescents with asthma reported that, among patients taking a combination of an inhaled corticosteroid and salmeterol, the addition of tiotropium increased lung function, reduced the rate of flare-ups, and improved asthma symptom control.6

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Monoclonal antibody therapy for severe asthma

Three monoclonal antibody therapies (omalizumab, mepolizumab and benralizumab) are available in Australia for the treatment of patients with severe asthma whose asthma is uncontrolled despite optimised standard treatment including high-dose inhaled corticosteroids and long-acting beta2 agonists.

Table. Monoclonal antibody therapies currently available in Australia for severe asthma

Name Description Indication*

Dosage & route of

administration

Benralizumab (Fasenra)

Anti-IL-5 receptor

Humanised monoclonal antibody directed against IL-5 receptor Rα on surface of eosinophils and basophils

Add-on treatment for uncontrolled severe eosinophilic asthma in adults and adolescents aged ≥ 12 years

Prefilled syringe for SC injection

30 mg SC every 4 weeks for three injections then every 8 weeks
Mepolizumab (Nucala)

Anti-IL-5

Humanised monoclonal antibody directed against IL-5
Add-on treatment for uncontrolled severe eosinophilic asthma in adults and adolescents ≥12 years

Powder for SC injection in a single-use vial

100 mg SC every 4 weeks
Omalizumab (Xolair)

Anti-IgE

Humanised monoclonal antibody directed against IgE

Add-on treatment for uncontrolled severe allergic asthma in adults, adolescents and children aged ≥6 years

Prefilled syringe for SC injection

Dose calculated according to baseline IgE and body weight. Usual dose every 2–4 weeks (larger doses divided in 2 and administered every 2 weeks)

SC: subcutaneous

*Refer to TGA-approved indications and PBS criteria

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Monoclonal antibody therapy reduces the rate of severe flare-ups requiring systemic corticosteroids.10, 1112, 13, 14, 15, 16, 1718, 19, 20 Many patients also experience improvement in asthma symptoms10, 11, 13, 14, 1517, 20, 21, 22 and quality of life.10, 15, 16, 23 Some studies have also shown a reduction in oral corticosteroid in patients with severe asthma.10, 11, 24, 15, 19, 20

These therapies are generally well tolerated.10, 13, 14, 18, 25 Injection site reactions are among the most common adverse events. Systemic reactions, including anaphylaxis, are rare but can occur.26

Monoclonal antibody therapies are funded by PBS only when prescribed by specialists (respiratory physician, clinical immunologist, allergist or general physician or paediatrician experienced in severe asthma management), for patients attending a public or private hospital, and when patients meet certain general and product-specific criteria. After treatment is initiated by a specialist, ongoing maintenance doses can be administered in primary care, but regular review for continuing PBS-funded treatment must be carried out by the specialist.

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Azithromycin for moderate-to-severe-asthma

Macrolide antibiotics have both anti-inflammatory effects and antimicrobial effects.  Azithromycin and clarithromycin are used in the management of cystic fibrosis,27 bronchiectasis28 and COPD29 to reduce exacerbation rates.

Efficacy in asthma

The role of macrolides in the treatment of severe asthma is uncertain.29, 30 The long-term use of azithromycin in adults with severe asthma may reduce flare-ups and improve symptom control, based on limited evidence.5

An Australian placebo-controlled randomised controlled trial reported that 48 weeks’ treatment with azithromycin 500 mg three times weekly reduced flare-ups and improved quality of life in adults with symptomatic asthma despite treatment with a moderate or high dose of inhaled corticosteroid and long-acting bronchodilator.31 Although long-term macrolide therapy was initially expected to be of most benefit patients with neutrophilic asthma, in this study a significant reduction in exacerbations was seen both in patients with eosinophilic and those with non-eosinophilic asthma. The greatest benefit was in those with positive bacterial culture. The study reported a nonsignificant increase in azithromycin-resistant organisms in sputum of patients treated with azithromycin, compared with placebo, but it was not adequately powered to fully assess this effect.

An earlier 6-month placebo-controlled randomised controlled trial in patients with severe asthma reported that low-dose azithromycin added to inhaled corticosteroids and long-acting beta2 agonist improved quality of life, but did not reduce the rate of severe flare-ups, improve asthma control or improve lung function.24 However, among the subgroup of patients with non-eosinophilic severe asthma, azithromycin significantly reduced the rate of a combined endpoint of either severe flare-ups or lower respiratory tract infections requiring antibiotics.24 Azithromycin was associated with an increased rate of oropharyngeal carriage of macrolide-resistant streptococci.24

Compared with standard doses for infections, macrolide doses evaluated in studies of long-term asthma treatment are generally lower.

The evidence for the use of macrolides in children and adolescents with severe asthma is limited and inconclusive due to a lack of completed trials.5

Safety

Although azithromycin is generally well tolerated, rare adverse effects include QTc prolongation and hearing impairment.32 Patients with either of these problems were excluded from the randomised controlled trials assessing the use of azithromycin in the treatment of moderate-to-severe or severe asthma.24, 31

There are also concerns about the potential for development of resistance. Specialist advice is recommended, including consultation with a local infectious diseases expert, before prescribing macrolides for asthma.

Atypical mycobacterial infections, hearing impairment and prolonged QT interval should be ruled out before prescribing. Treatment-related adverse effects should be monitored by ECG, audiology and liver function tests.

Note: Azithromycin and clarithromycin are not registered by the TGA for the long-term treatment of asthma.

Note: Azithromycin is not subsidised by the PBS for long-term use.

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Ipratropium in acute asthma

Adults

In adults and older adolescents with severe acute asthma treated in the emergency department, the combination of ipratropium and short-acting beta2 agonist reduces hospitalisation rate and improves lung function, compared with short-acting beta2 agonist alone.33 Hospitalisation rates are not reduced in patients with mild or moderate acute asthma.33

In adults, the combination of ipratropium and short-acting beta2 agonist is associated with a higher rate of adverse effects (e.g. tremor, agitation, and palpitations) than short-acting beta2 agonist alone.33

Children

Recent systematic reviews have reported that initial treatment with ipratropium in addition to salbutamol markedly reduces hospitalisation rate and improves clinical scores in children with moderate to severe acute asthma.34, 35, 36

However, in children hospitalised due to acute asthma, the combination of ipratropium and short-acting beta2 agonist was not more effective than short-acting beta2 agonist alone.37

The combination of ipratropium and short-acting beta2 agonist appears to be well tolerated in children.36

Ipratropium bromide alone is less effective than salbutamol alone in acute asthma.38

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Magnesium sulfate in acute asthma

Magnesium sulfate in acute asthma

Clinical trial evidence does not support the use of magnesium sulfate as a substitute for inhaled beta2 agonists.39

Its main use is in addition to salbutamol, either in combination with initial bronchodilator treatment, or as an add-on treatment in patients with inadequate response to initial bronchodilator treatment.

Intravenous magnesium sulfate

Adults

IV magnesium sulfate may have a small effect in reducing hospital admissions and may improve lung function in adults with acute asthma who have failed to respond to standard treatment.40, 41

In a large, well-conducted randomised controlled trial in adults with moderate-to-severe acute asthma treated in an emergency department (excluding those with life-threatening asthma), IV magnesium sulfate improved dyspnoea scores but did not reduce hospital admission rates.42

Current evidence does not indicated whether or not IV magnesium sulfate is more effective for patients with a more severe acute asthma.40

The optimal dose and infusion regimen has not been identified.40

IV magnesium sulfate IV appears to be well tolerated in adults.40 Minor flushing is the most common adverse event.40 Other adverse effects reported in clinical trials include fatigue, nausea, headache and hypotension.41

Children

IV magnesium sulfate may reduce hospitalisation rates and improve lung function among children with acute asthma in presenting to the emergency department,43, 44 but there is limited evidence.44

A small randomised controlled trial reported that IV magnesium sulfate was ineffective in reducing respiratory distress in very young children (6 months to 4 years) with acute virus-induced wheezing.45

IV magnesium sulfate is generally well tolerated.44, 46

Nebulised magnesium sulfate

Nebulised magnesium sulfate may achieve small additional improvement in lung function and reduction in hospital admission rates when added to salbutamol and ipratropium in adults and children with acute asthma, but these benefits have not been clearly demonstrated on current evidence.39

Randomised controlled trials have reported conflicting findings. The larger and more recent studies typically show a smaller effect than some of the older, smaller studies.39 Large, well-designed trials in adults42, 47 and children48, 49, 50 have generally not demonstrated clinically important benefits.39 A systematic review of randomised controlled trials found no overall improvement in lung function when magnesium sulfate was added to salbutamol and ipratropium.39

Nebulised magnesium sulfate is well tolerated and does not appear to be associated with an increase in serious adverse events.39

Adults

It is uncertain whether nebulised magnesium sulfate improves lung function or symptoms, or reduces hospital admissions, when added to standard treatment in adults.40

Some studies suggest that patients presenting with severe acute asthma may benefit, but the data are not conclusive.40

A large, well-designed RCT showed no reduction in hospitalisation or dyspnoea rates in adults with acute asthma given add-on nebulised magnesium, compared with standard therapy alone,42, 47 but this study excluded patients with life-threatening acute asthma.

Children

A recent systematic review found that nebulised magnesium sulfate had no effect on hospitalisation rates or lung function in children with acute asthma.43

However, one large, well-designed randomised controlled trial in children reported that nebulised magnesium sulfate was associated with a small improvement in asthma symptom scores at 60 minutes. The effect was greatest in the subgroups of children with more severe acute asthma (SaO2<92%), and those with more sudden onset (symptoms less than 6 hours before acute attack).48, 49

Nebulised magnesium sulfate is well tolerated in children.48, 49

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Theophyllines in acute asthma

Few studies have compared IV aminophylline with IV short-acting beta2 agonist in the management of acute asthma in adults and children.

Compared with salbutamol IV aminophylline is associated with a higher rate of adverse effects including giddiness, nausea and vomiting.51

It is used mainly as an add-on therapy when there is inadequate response to initial bronchodilator.

Aminophylline plus salbutamol in adults

Overall, evidence from randomised clinical trials in adults with acute asthma treated in emergency departments suggests that intravenous aminophylline given in addition to inhaled beta2 agonists does not achieve greater bronchodilation or reduce hospital admissions, compared with inhaled beta2 agonists alone.52 No sub-groups that benefit from intravenous aminophylline have been clearly identified.52

Aminophylline is associated with vomiting and cardiac arrhythmias.52

Theophylline is metabolised mainly by the liver and commonly interacts with other medicines. Its concentration in plasma should be monitored closely in older people or those with comorbid conditions.53

Aminophylline plus salbutamol in children

In children with acute asthma requiring hospital admission, the addition of intravenous aminophylline to beta2-agonists and corticosteroids (with or without ipratropium) may improve lung function within 6 hours of treatment, but does not appear to improve symptoms or shorten hospital stay.54

The optimal aminophylline dose in children has not been clearly identified. Evidence from clinical trials does not show a clear association between dose and clinical outcomes.55

Aminophylline is associated with a significant increased risk of vomiting in children.54 The rate of adverse effects appears to be higher among children receiving higher loading doses of IV aminophylline (7–10 mg/kg), compared with 5–6 mg/kg.55

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Roles of adrenaline in the management of acute asthma

Adrenaline is not used routinely in the management of severe acute asthma.

Its use should be reserved for situations where inhaled salbutamol cannot be given in a patient with respiratory arrest or pre-arrest status, or when anaphylaxis is suspected.

Anaphylaxis

Anaphylaxis is rare among people with acute asthma. An estimated 3.4% of adults admitted to the intensive care unit for acute severe asthma also meet criteria for anaphylaxis, according to one retrospective study56

Intramuscular adrenaline (or intravenous adrenaline in clinical settings with appropriately trained staff) is indicated for patients with anaphylaxis and angioedema, and patients with known allergies to food or other relevant allergens (other than aeroallergens) who have sudden-onset breathing problems, even if they have no other signs of anaphylaxis.57

Australasian Society of Clinical Immunology and Allergy recommends that adrenaline should be given before bronchodilators for a patient with sudden-onset breathing problems and known allergy to foods, insects or medicines.57

Asthma

Few studies have compared adrenaline in addition to, or in comparison with, currently recommended bronchodilator treatment in patients with acute asthma, either in hospital emergency departments or pre-hospital acute services.

Hospital or emergency department setting

Nebulised adrenaline

Nebulised adrenaline does not have a significant benefit over salbutamol or terbutaline in the management of moderate-to-severe acute asthma in adults and children.58

Intramuscular, intravenous or subcutaneous adrenaline

Adrenaline given IV, subcutaneously or intramuscularly has no benefit over inhaled short-acting beta2 agonists in the management of acute asthma.59, 60, 61, 62

Three small clinical trials comparing subcutaneous adrenaline with nebulised salbutamol in children with acute asthma reported equivalent respiratory outcomes including peak expiratory flow rate.59, 60, 61 Adrenaline was associated with higher rates of adverse effects, including a short-term increase in systolic blood pressure and heart rate.59, 60

Another trial in children with acute asthma reported that subcutaneous adrenaline was more effective than nebulised terbutaline in increasing oxygen saturation and FEV1, but was associated with a higher rate of adverse events including pallor, tremor, dizziness, headache, palpitation, soreness of legs, numbness of extremities, cold sweating, general weakness and nausea.63

A clinical trial comparing subcutaneous adrenaline with nebulised terbutaline in adults with acute asthma reported equivalent efficacy.62 The adrenaline group, but not the terbutaline group, showed an increase in pulse rate.62 A non-comparative retrospective study of 220 adults who had received IV adrenaline for acute asthma reported that adverse events were common but mostly minor and self-limiting.64 Major adverse events occurred in approximately 4% of patients and included 2 cases of supraventricular tachycardia, 1 case of chest pain with ECG changes, 1 case of incidental elevated troponin, and 4 cases of hypotension requiring intervention.64

Prehospital setting

There is limited evidence to guide the use of adrenaline in patients with acute asthma in the prehospital setting. However, it has no benefit over inhaled salbutamol in patients with acute asthma and is associated with a worse adverse effect profile.

Subcutaneous adrenaline was associated with increased heart rate and increased blood pressure, compared with a nebulised bronchodilator (metaproterenol), in a randomised controlled trial in adults presenting to ambulance services with acute asthma.65

In some states, ambulance services give adrenaline to patients with severe, life-threatening acute asthma. In this circumstance inhaled/nebulised salbutamol is preferable initially. When there is an inadequate response with acute and rapid deterioration or when the inhaled route is impractical because the person is not breathing, some ambulance protocols recommend administration of either IM Adrenaline (500 mg, 1:1000), if needed at intervals of 5–10 minutes or IV adrenaline 50–100 mg at intervals of 2–5 minutes.66

Ventilation must be adequately supported. If cardiac or respiratory arrest occurs, appropriate resuscitation procedures should be followed.67

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Role of ketamine in acute asthma

Ketamine has been proposed by some researchers as a suitable option for pre-intubation sedation in patients with respiratory failure caused by acute asthma (where not contraindicated) because it stimulates the release of catecholamines and may contribute to bronchodilation through direct relaxation effect on bronchial smooth muscle.68

Evidence does not strongly support the use of ketamine in non-intubated children with acute asthma.69 The results of small studies suggest that ketamine at a dose of approximately 1 mg/kg may have some benefit in bronchodilation and clinical symptoms in children.70 However, benefits compared with other add-on treatments for acute asthma and long-term effects have not been established.70 In children with acute asthma who have an inadequate response to initial bronchodilator therapy, the effect of IV ketamine on respiratory status may be equivalent to that to that of IV aminophylline.71

Adverse effects associated with ketamine include hypersecretion, hypotension and hypertension, arrhythmias, and hallucinations.68

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Antibiotics in acute asthma

Antibiotics are not used routinely in the management of acute asthma but should be used if they would otherwise be indicated.

The role of atypical bacterial infections (e.g. Chlamydophyla pneumonia, Mycoplasma pneumonae) in asthma is under investigation. Atypical bacterial infections may make acute asthma more severe, especially in patients with poorly controlled asthma. Macrolide antibiotics are active against atypical bacteria and have anti-inflammatory activity. However, their potential anti-inflammatory effects in the treatment of acute asthma have not been well studied.

A systematic review72 of antibiotic treatment in asthma flare-ups found that the few available randomised controlled trials were heterogeneous and that their findings were inconsistent. It  concluded that there was limited evidence that antibiotics given at the time of an asthma flare-up may improve symptoms and lung function at follow‐up, compared with standard care or placebo.72

The systematic review identified four studies that assessed the use of macrolide antibiotics in the management of asthma flare-ups. Combined results for two of these (416 participants) showed that macrolide treatment was associated with improvement in symptoms.72 One included study reported an increase in symptoms-free days at 10 days in adults treated with a macrolide, compared with placebo, which was independent of serological evidence for infection with chlamydia pneumonia or mycoplasma pneumoniae. However, the study drug (telithromycin) is no longer in use due to its association with severe liver toxicity.

In a study of adults attending emergency care for acute asthma, treatment with azithromycin 500 mg per day for 3 days was not associated with an improvement in symptoms or lung function, compared with placebo.73 However, 1 in 10 participants assessed for this trial were excluded as they had already commenced an antibiotic at the time of screening.

In a study of children aged 1–5 years presenting to the emergency department with acute wheezing illness,74 children were randomised to either azithromycin for 5 days or placebo. Azithromycin treatment did not reduce the duration of respiratory symptoms or the time to a respiratory flare-up in the following 6 months after treatment.74

A small (n=40) study assessing clarithromycin treatment in children aged 1–3 years with acute wheezing illness reported an increase in symptoms-free days at 3, 6 and 12 weeks, compared with usual care.75

The systematic review of antibiotic treatment in asthma flare-ups72 included two studies investigating penicillin treatment in patients admitted to hospital with asthma. Neither observed a significant difference in duration of admission, and one reported no difference in asthma symptoms at discharge.72

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References

  1. McDonald N, Bara A, McKean MC. Anticholinergic therapy for chronic asthma in children over two years of age. Cochrane Database Syst Rev. 2003; Issue 1: CD003535. Available from: http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD003535/full
  2. Westby M, Benson M, Gibson P. Anticholinergic agents for chronic asthma in adults. Cochrane Database Syst Rev. 2004; Issue 3: CD003269. Available from: http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD003269.pub2/full
  3. Rodrigo GJ, Neffen H. Efficacy and safety of tiotropium in school-age children with moderate-to-severe symptomatic asthma: A systematic review. Pediatr Allergy Immunol 2017; 28: 573-8. Available from: https://www.ncbi.nlm.nih.gov/pubmed/28692145
  4. Boehringer Ingelheim Pty Limited,. Product Information: Spiriva (tiotropium bromide) Respimat.. Therapeutic Goods Administration, Canberra, 2018. Available from: https://www.ebs.tga.gov.au/
  5. FitzGerald, JM, Lemiere, C, Lougheed, M D, et al. Recognition and management of severe asthma: a Canadian Thoracic Society position statement. Can J Respir Crit Care Med. 2017; 1: 199-221. Available from: https://www.tandfonline.com/doi/full/10.1080/24745332.2017.1395250
  6. Rodrigo, G. J., Castro-Rodriguez, J. A.. Tiotropium for the treatment of adolescents with moderate to severe symptomatic asthma: a systematic review with meta-analysis. Ann Allergy Asthma Immunol. 2015; 115: 211-6. Available from: https://www.ncbi.nlm.nih.gov/pubmed/26231467
  7. Anderson, D. E., Kew, K. M., Boyter, A. C.. Long-acting muscarinic antagonists (LAMA) added to inhaled corticosteroids (ICS) versus the same dose of ICS alone for adults with asthma. Cochrane Database Syst Rev. 2015; : CD011397. Available from: http://cochranelibrary-wiley.com/doi/10.1002/14651858.CD011397.pub2/full
  8. Sobieraj, D. M., Baker, W. L., Nguyen, E., et al. Association of inhaled corticosteroids and long-acting muscarinic antagonists with asthma control in patients with uncontrolled, persistent asthma: a systematic review and meta-analysis. JAMA. 2018; 319: 1473-1484. Available from: https://www.ncbi.nlm.nih.gov/pubmed/29554174
  9. Kew, K. M., Dahri, K.. Long-acting muscarinic antagonists (LAMA) added to combination long-acting beta2-agonists and inhaled corticosteroids (LABA/ICS) versus LABA/ICS for adults with asthma. Cochrane Database Syst Rev. 2016; : CD011721. Available from: http://cochranelibrary-wiley.com/doi/10.1002/14651858.CD011721.pub2/full
  10. Nair, P., Wenzel, S., Rabe, K. F., et al. Oral glucocorticoid-sparing effect of benralizumab in severe asthma. N Engl J Med. 2017; 376: 2448-2458. Available from: http://www.nejm.org/doi/full/10.1056/NEJMoa1703501
  11. Bel, E. H., Wenzel, S. E., Thompson, P. J., et al. Oral glucocorticoid-sparing effect of mepolizumab in eosinophilic asthma. N Engl J Med. 2014; 371: 1189-97. Available from: http://www.nejm.org/doi/full/10.1056/NEJMoa1403291
  12. Yancey, S. W., Ortega, H. G., Keene, O. N., et al. Meta-analysis of asthma-related hospitalization in mepolizumab studies of severe eosinophilic asthma. J Allergy Clin Immunol. 2017; 139: 1167-1175.e2. Available from: http://www.jacionline.org/article/S0091-6749(16)30891-0/fulltext
  13. Bleecker, E. R., FitzGerald, J. M., Chanez, P., et al. Efficacy and safety of benralizumab for patients with severe asthma uncontrolled with high-dosage inhaled corticosteroids and long-acting beta2-agonists (SIROCCO): a randomised, multicentre, placebo-controlled phase 3 trial. Lancet. 2016; 388: 2115-2127. Available from: https://www.ncbi.nlm.nih.gov/pubmed/27609408
  14. FitzGerald, J. M., Bleecker, E. R., Nair, P., et al. Benralizumab, an anti-interleukin-5 receptor alpha monoclonal antibody, as add-on treatment for patients with severe, uncontrolled, eosinophilic asthma (CALIMA): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2016; 388: 2128-2141. Available from: https://www.ncbi.nlm.nih.gov/pubmed/27609406
  15. Abraham, I., Alhossan, A., Lee, C. S., et al. 'Real-life' effectiveness studies of omalizumab in adult patients with severe allergic asthma: systematic review. Allergy. 2016; 71: 593-610. Available from: https://onlinelibrary.wiley.com/doi/epdf/10.1111/all.12815
  16. Wang, F. P., Liu, T., Lan, Z., et al. Efficacy and safety of anti-interleukin-5 therapy in patients with asthma: a systematic review and meta-analysis. PloS One. 2016; 11: e0166833. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5119789
  17. Ortega, H. G., Liu, M. C., Pavord, I. D., et al. Mepolizumab treatment in patients with severe eosinophilic asthma. N Engl J Med. 2014; 371: 1198-207. Available from: http://www.nejm.org/doi/full/10.1056/NEJMoa1403290
  18. Normansell, R, Walker, S, Milan, S J, et al. Omalizumab for asthma in adults and children. Cochrane Database Syst Rev. 2014; Issue 1: Art. No.: CD003559. Available from: https://www.ncbi.nlm.nih.gov/pubmed/24414989
  19. Norman, G., Faria, R., Paton, F., et al. Omalizumab for the treatment of severe persistent allergic asthma: a systematic review and economic evaluation. Health Technol Assess. 2013; 17: 1-342. Available from: https://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0083500/
  20. Braunstahl, G. J., Chen, C. W., Maykut, R., et al. The eXpeRience registry: the 'real-world' effectiveness of omalizumab in allergic asthma. Respir Med. 2013; 107: 1141-51. Available from: http://www.resmedjournal.com/article/S0954-6111(13)00167-4/fulltext
  21. Humbert, M., Taille, C., Mala, L., et al. Omalizumab effectiveness in patients with severe allergic asthma according to blood eosinophil count: the STELLAIR study. Eur Respir J. 2018; 51: . Available from: http://erj.ersjournals.com/content/51/5/1702523.long
  22. Gibson, P. G., Reddel, H., McDonald, V. M., et al. Effectiveness and response predictors of omalizumab in a severe allergic asthma population with a high prevalence of comorbidities: the Australian Xolair Registry. Intern Med J. 2016; 46: 1054-62. Available from: https://www.ncbi.nlm.nih.gov/pubmed/27350385
  23. Lai, T., Wang, S., Xu, Z., et al. Long-term efficacy and safety of omalizumab in patients with persistent uncontrolled allergic asthma: a systematic review and meta-analysis. Sci Rep. 2015; 5: 8191. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4314644/
  24. Brusselle, G. G., Vanderstichele, C., Jordens, P., et al. Azithromycin for prevention of exacerbations in severe asthma (AZISAST): a multicentre randomised double-blind placebo-controlled trial. Thorax. 2013; 68: 322-9. Available from: https://www.ncbi.nlm.nih.gov/pubmed/23291349
  25. Farne, H. A., Wilson, A., Powell, C., et al. Anti-IL5 therapies for asthma. Cochrane Database Syst Rev. 2017; Issue 9: CD010834. Available from: http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD010834.pub3/full
  26. Loprete, J N, Katelaris, C H. Hypersensitivity reactions to monoclonal antibody treatments for immune disorders. Medicine Today. 2018; 19: 55-60. Available from: https://medicinetoday.com.au/2018/january/regular-series/hypersensitivity-reactions-monoclonal-antibody-treatments-immune
  27. Southern, K. W., Barker, P. M., Solis-Moya, A., Patel, L.. Macrolide antibiotics for cystic fibrosis. Cochrane Database Syst Rev. 2012; 11: Cd002203. Available from: https://www.ncbi.nlm.nih.gov/pubmed/23152214
  28. Kelly, C., Chalmers, J. D., Crossingham, I., et al. Macrolide antibiotics for bronchiectasis. Cochrane Database Syst Rev. 2018; 3: Cd012406. Available from: https://www.ncbi.nlm.nih.gov/pubmed/29543980
  29. Papi, A., Brightling, C., Pedersen, S. E., Reddel, H. K.. Asthma. Lancet. 2018; 391: 783-800. Available from: https://www.ncbi.nlm.nih.gov/pubmed/29273246
  30. Kew, K. M., Undela, K., Kotortsi, I., Ferrara, G.. Macrolides for chronic asthma. Cochrane Database Syst Rev. 2015; : Cd002997. Available from: https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD002997.pub4/full
  31. Gibson, P. G., Yang, I. A., Upham, J. W., et al. Effect of azithromycin on asthma exacerbations and quality of life in adults with persistent uncontrolled asthma (AMAZES): a randomised, double-blind, placebo-controlled trial. Lancet. 2017; 390: 659-668. Available from: https://www.ncbi.nlm.nih.gov/pubmed/28687413
  32. Australian Medicines Handbook. Last modified July 2018: Australian Medicines Handbook Pty Ltd. 2018
  33. Kirkland SW, Vandenberghe C, Voaklander B et al. Combined inhaled beta-agonist and anticholinergic agents for emergency management in adults with asthma. Cochrane Database Syst Rev. 2017; Issue 1: CD001284. Available from: https://www.ncbi.nlm.nih.gov/pubmed/28076656
  34. Castro-Rodriguez, J. A., Rodrigo, G. J., Rodriguez-Martinez, C. E.. Principal findings of systematic reviews for chronic treatment in childhood asthma. J Asthma. 2015; 52: 1038-45. Available from: https://www.ncbi.nlm.nih.gov/pubmed/26303207
  35. Pollock M, Sinha IP, Hartling L et al. Inhaled short-acting bronchodilators for managing emergency childhood asthma: an overview of reviews. Allergy. 2017; 72: 183-200. Available from: https://www.ncbi.nlm.nih.gov/pubmed/27588581
  36. Griffiths B, Ducharme FM. Combined inhaled anticholinergics and short-acting beta2-agonists for initial treatment of acute asthma in children. Cochrane Database Syst Rev. 2013: Cd000060. Available from: https://www.ncbi.nlm.nih.gov/pubmed/23966133
  37. Vezina K, Chauhan BF, Ducharme FM. Inhaled anticholinergics and short-acting beta(2)-agonists versus short-acting beta2-agonists alone for children with acute asthma in hospital.Cochrane Database Syst Rev. 2014; Issue 7: CD010283. Available from: https://www.ncbi.nlm.nih.gov/pubmed/25080126/
  38. Teoh L, Cates CJ, Hurwitz M, et al. Anticholinergic therapy for acute asthma in children. Cochrane Database Syst Rev. 2012; 4: CD003797. Available from: http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD003797.pub2/full
  39. Knightly R, Milan SJ, Hughes R et al. Inhaled magnesium sulfate in the treatment of acute asthma. Cochrane Database Syst Rev 2017; 11: Cd003898. Available from: https://www.ncbi.nlm.nih.gov/pubmed/29182799/
  40. Green RH. Asthma in adults (acute): magnesium sulfate treatment. BMJ Clin Evid 2016; 2016: Available from:https://www.ncbi.nlm.nih.gov/pubmed/26761432/
  41. Kew KM, Kirtchuk L, Michell CI. Intravenous magnesium sulfate for treating adults with acute asthma in the emergency department. Cochrane Database Syst Rev 2014: Cd010909. Available from: https://www.ncbi.nlm.nih.gov/pubmed/24865567/
  42. Goodacre S, Cohen J, Bradburn M et al. The 3Mg trial: a randomised controlled trial of intravenous or nebulised magnesium sulphate versus placebo in adults with acute severe asthma. Health Technol Assess 2014; 18: 1-168. Available from: https://www.ncbi.nlm.nih.gov/pubmed/24731521/
  43. Su Z, Li R, Gai Z. Intravenous and nebulized magnesium sulfate for treating acute asthma in children: a systematic review and meta-analysis. Pediatr Emerg Care 2018; 34: 390-5. Available from: https://www.ncbi.nlm.nih.gov/pubmed/29851914/
  44. Griffiths B, Kew KM. Intravenous magnesium sulfate for treating children with acute asthma in the emergency department. Cochrane Database Syst Rev 2016; 4: Cd011050. Available from: https://www.ncbi.nlm.nih.gov/pubmed/27126744/
  45. Pruikkonen H, Tapiainen T, Kallio M et al. Intravenous magnesium sulfate for acute wheezing in young children: a randomised double-blind trial. Eur Respir J 2018; 51: Available from: https://www.ncbi.nlm.nih.gov/pubmed/29437941/
  46. Irazuzta JE, Chiriboga N. Magnesium sulfate infusion for acute asthma in the emergency department. J Pediatr (Rio J) 2017; 93 Suppl 1: 19-25. Available from: https://www.ncbi.nlm.nih.gov/pubmed/28754601/
  47. Goodacre S, Cohen J, Bradburn M et al. Intravenous or nebulised magnesium sulphate versus standard therapy for severe acute asthma (3Mg trial): a double-blind, randomised controlled trial. Lancet Respir Med 2013; 1: 293-300. Available from: https://www.ncbi.nlm.nih.gov/pubmed/24429154/
  48. Powell C, Kolamunnage-Dona R, Lowe J, et al. MAGNEsium Trial In Children (MAGNETIC): a randomised, placebo-controlled trial and economic evaluation of nebulised magnesium sulphate in acute severe asthma in children. Health Technol Assess. 2013; 17: 1-216. Available from: http://www.ncbi.nlm.nih.gov/pubmed/24144222
  49. Powell C, Kolamunnage-Dona R, Lowe J et al. Magnesium sulphate in acute severe asthma in children (MAGNETIC): a randomised, placebo-controlled trial. Lancet Respir Med 2013; 1: 301-8. Available from: https://www.ncbi.nlm.nih.gov/pubmed/24429155/
  50. Alansari K, Ahmed W, Davidson BL et al. Nebulized magnesium for moderate and severe pediatric asthma: A randomized trial. Pediatr Pulmonol 2015; 50: 1191-9. Available from: https://www.ncbi.nlm.nih.gov/pubmed/25652104/
  51. Travers AH, Jones AP, Camargo CA et al. Intravenous beta2-agonists versus intravenous aminophylline for acute asthma. Cochrane Database Syst Rev 2012; Issue 12: CD010256. Available from:https://www.ncbi.nlm.nih.gov/pubmed/23235686/
  52. Nair P, Milan SJ, Rowe BH. Addition of intravenous aminophylline to inhaled beta2-agonists in adults with acute asthma. Cochrane Database Syst Rev 2012; Issue 12: CD002742. Available from: https://www.ncbi.nlm.nih.gov/pubmed/23235591/
  53. Gupta P, O'Mahony MS. Potential adverse effects of bronchodilators in the treatment of airways obstruction in older people: recommendations for prescribing. Drugs Aging. 2008; 25: 415-43.
  54. Mitra AA, Bassler D, Watts K, et al. Intravenous aminophylline for acute severe asthma in children over two years receiving inhaled bronchodilators. Cochrane Database Syst Rev. 2005; Issue 2: CD001276. Available from: https://www.ncbi.nlm.nih.gov/pubmed/15846615
  55. Cooney L, Sinha I, Hawcutt D. Aminophylline dosage in asthma exacerbations in children: a systematic review. PLoS One 2016; 11: e0159965. Available from: https://www.ncbi.nlm.nih.gov/pubmed/27483163/
  56. Akenroye AT, Ajala A, Azimi-Nekoo E, de Vos GS. Prevalence of anaphylaxis among adults admitted to critical care for severe asthma exacerbation. Emerg Med J 2018: Available from: https://www.ncbi.nlm.nih.gov/pubmed/30093380/
  57. Australasian Society of Clinical Immunology and Allergy. Guidelines. Acute management of anaphylaxis: ASCIA. 2017. Available from: https://www.allergy.org.au/images/stories/pospapers/ASCIA_Guidelines_Acute_Management_Anaphylaxis_2017_Updated.pdf/.
  58. Rodrigo GJ, Nannini LJ. Comparison between nebulized adrenaline and beta2 agonists for the treatment of acute asthma. A meta-analysis of randomized trials. Am J Emerg Med 2006; 24: 217-22. Available from: https://www.ncbi.nlm.nih.gov/pubmed/16490653/
  59. Sharma A, Madan A. Subcutaneous epinephrine vs nebulized salbutamol in asthma. Indian J Pediatr 2001; 68: 1127-30. Available from: https://www.ncbi.nlm.nih.gov/pubmed/11838566/
  60. Becker AB, Nelson NA, Simons FE. Inhaled salbutamol (albuterol) vs injected epinephrine in the treatment of acute asthma in children. J Pediatr 1983; 102: 465-9. Available from: https://www.ncbi.nlm.nih.gov/pubmed/6827423/
  61. Kornberg AE, Zuckerman S, Welliver JR et al. Effect of injected long-acting epinephrine in addition to aerosolized albuterol in the treatment of acute asthma in children. Pediatr Emerg Care 1991; 7: 1-3. Available from: https://www.ncbi.nlm.nih.gov/pubmed/2027802/
  62. Baughman RP, Ploysongsang Y, James W. A comparative study of aerosolized terbutaline and subcutaneously administered epinephrine in the treatment of acute bronchial asthma. Ann Allergy 1984; 53: 131-4. Available from: https://www.ncbi.nlm.nih.gov/pubmed/6465622/
  63. Lin YZ, Hsieh KH, Chang LF, Chu CY. Terbutaline nebulization and epinephrine injection in treating acute asthmatic children. Pediatr Allergy Immunol 1996; 7: 95-9. Available from: https://www.ncbi.nlm.nih.gov/pubmed/8902860/
  64. Putland M, Kerr D, Kelly A. Adverse events associated with the use of intravenous epinephrine in emergency department patients presenting with severe asthma. Ann Emerg Med 2006; 14: 559-63. Available from: https://www.ncbi.nlm.nih.gov/pubmed/16713785/
  65. Quadrel M, Lavery RF, Jaker M et al. Prospective, randomized trial of epinephrine, metaproterenol, and both in the prehospital treatment of asthma in the adult patient. Ann Emerg Med 1995; 26: 469-73. Available from: https://www.ncbi.nlm.nih.gov/pubmed/7574130/
  66. Ambulance Victoria. Clinical practice guidelines for ambulance and MICA paramedics. 2018 edition version 1.4. Melbourne: Ambulance Victoria; 2017. Available from: https://www.ambulance.vic.gov.au/paramedics/clinical-practice-guidelines/
  67. Australian and New Zealand Committee on Resuscitation. ANZCOR Guideline 9.2.7 – First aid management of anaphylaxis. Australian Resuscitation Council; 2016 [September 2018]; Available from: https://resus.org.au/guidelines/
  68. Brenner B, Corbridge T, Kazzi A. Intubation and mechanical ventilation of the asthmatic patient in respiratory failure. Proc Am Thorac Soc. 2009; 6: 371-379. Available from: http://www.atsjournals.org/doi/full/10.1513/pats.P09ST4
  69. Jat KR, Chawla D. Ketamine for management of acute exacerbations of asthma in children. Cochrane Database Syst Rev. 2012; 11: CD009293. Available from: http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD009293.pub2/full
  70. Rehder KJ. Adjunct therapies for refractory status asthmaticus in children. Respir Care 2017; 62: 849-65. Available from: https://www.ncbi.nlm.nih.gov/pubmed/28546381/
  71. Tiwari A, Guglani V, Jat KR. Ketamine versus aminophylline for acute asthma in children: A randomized, controlled trial. Annals of thoracic medicine 2016; 11: 283-8. Available from: https://www.ncbi.nlm.nih.gov/pubmed/27803755/
  72. Normansell R, Sayer B, Waterson S et al. Antibiotics for exacerbations of asthma. Cochrane Database Syst Rev 2018; 6: CD002741. Available from: https://www.ncbi.nlm.nih.gov/pubmed/29938789/
  73. Johnston SL, Szigeti M, Cross M et al. Azithromycin for acute exacerbations of asthma : the AZALEA randomized clinical trial. JAMA Intern Med 2016; 176: 1630-7. Available from: https://www.ncbi.nlm.nih.gov/pubmed/27653939/.
  74. Mandhane PJ, Paredes Zambrano de Silbernagel P, Aung YN et al. Treatment of preschool children presenting to the emergency department with wheeze with azithromycin: A placebo-controlled randomized trial. PloS One 2017; 12: e0182411. Available from: https://www.ncbi.nlm.nih.gov/pubmed/28771627/
  75. Koutsoubari I, Papaevangelou V, Konstantinou GN, et al. Effect of clarithromycin on acute asthma exacerbations in children: an open randomized study. Pediatr Allergy Immunol. 2012; 23: 385-90. Available from: http://onlinelibrary.wiley.com/doi/10.1111/j.1399-3038.2012.01280.x/full