Asthma is the most common chronic disease of childhood1 and the most frequent cause of children being hospitalized.2 Despite advances in the treatment of asthma, these rates have remained constant or have increased in the past decade.3 This article gives an overview of the medications used in treating childhood asthma.
Table 1.
| Terms used in the MEDLINE search |
|---|
|
METHODS
For this review, I searched MEDLINE from 1966 to March 2000 using the search terms shown in the box. I limited my search to full-text English-language articles reporting the results of randomized controlled trials or systematic reviews. I considered the National Institutes of Health guidelines for the diagnosis and management of asthma and used a standard pharmacotherapy textbook as a resource.4
PATHOGENESIS AND OVERVIEW OF TREATMENT
Asthma is a disease of chronic inflammation and acute bronchospasm of the airways. The treatment of asthma focuses on the control of this inflammation and the relief of acute attacks.
The National Asthma Education and Prevention Program of the National Heart, Lung and Blood Institute (NHLBI) has compiled guidelines for asthma management. These outline the appropriate treatment of patients based on a stepwise approach to asthma severity and the patient's age (tables 1 and 2). They attempt to define first-line agents for anti-inflammatory control and the place of adjunctive therapies. The goal is to optimize pharmacotherapy to prevent chronic symptoms and exacerbations and to maintain pulmonary function and activity levels.3
Table 1.
Treatment of asthma in adults and children older than 5 years*
| Step | Long-term control | Quick relief |
|---|---|---|
| Step 4: Severe persistent |
|
Short-acting bronchodilator: inhaled β2-agonists as needed |
| Step 3: Moderate persistent |
|
Short-acting bronchodilator: inhaled β2-agonists as needed. If using >2 × /wk, consider increasing to the next step |
| Step 2: Mild persistent |
|
Short-acting bronchodilator: inhaled β2-agonists as needed. If using >2 × /wk, consider increasing to the next step |
| Step 1: Mild intermittent | No daily medication | Short-acting bronchodilator: inhaled β2-agonists as needed. If using >2 × /wk, consider increasing to the next step |
From the National Asthma Education and Prevention Program.3
Table 2.
Treatment of asthma in adults and children aged 5 years and younger*
| Step | Long-term control | Quick relief |
|---|---|---|
| Step 4: Severe persistent |
|
Short-acting bronchodilator: β2-agonists as needed (inhaled or oral) |
| Step 3: Moderate persistent | Anti-inflammatory drug: inhaled corticosteroid (medium dose) with or without nedocromil sodium or theophylline | Short-acting bronchodilator: β2-agonists as needed (inhaled or oral). If using >2 × /wk, consider increasing to the next step |
| Step 2: Mild persistent | Anti-inflammatory drug: mast cell stabilizer or inhaled corticosteroids (low dose) | Short-acting bronchodilator: β2-agonists as needed (inhaled or oral). If using >2 × /wk, consider increasing to the next step |
| Step 1: Mild intermittent | No daily medicines needed | Short-acting bronchodilator: β2-agonists as needed (inhaled or oral). If using >2 × /wk, consider increasing to the next step |
From the National Asthma Education and Prevention Program.3
PHARMACOLOGIC TREATMENT OF ASTHMA
Short-acting β-agonists
β-Agonists are sympathomimetic agents that relax the smooth muscles of the bronchioles by stimulating β2-adrenergic receptors. They also have activity at β1- and α-adrenergic receptors, and their use may result in side effects such as myocardial contractility, tachycardia, and vasoconstriction. Albuterol, the most frequently used agent, has a rapid onset of action, potent bronchodilator activity, and fewer side effects than other agents (table 3).
Table 3.
Short-acting bronchodilators for the treatment of asthma
| Drug | Onset of action, min | Duration, hr | Dosage |
|---|---|---|---|
| Albuterol | Inhaled: within 5; oral: within 30 | 4-8 | Inhaled: 2 puffs every 4-6 hr as needed; oral: 0.1 mg/kg 3-4 ×/d as needed |
| Metaproterenol sulfate | Inhaled: 5-30; oral: 30 | Inhaled: 2-6; oral: 4 | Inhaled: 2-3 puffs every 3-4 hr as needed; oral: 1.3-2.6 mg/kg/d, divided, 3-4 ×/d as needed |
| Terbutaline sulfate* | Inhaled: 5-30; oral: 30 | Inhaled: 3-6; oral: 4-8 | Inhaled: 2 puffs every 4-6 hr as needed; oral: 2.5-5.0 mg 3 ×/d as needed |
| Bitolterol mesylate* | Inhaled: 3-4 | Inhaled: 5-8 | Inhaled: 2 puffs every 8 hr as needed |
For patients aged 12 years and older.
The use of short-acting β-agonists as needed for acute exacerbations is a convenient method of assessing asthma control. More than twice-a-week use of albuterol is a sign to begin administering or increasing the dosage of anti-inflammatory medications.3
Bronchodilators can be administered through several routes, including an oral syrup, metered-dose inhaler (MDI), or a nebulizer. The syrup is rarely used because of its higher incidence of systemic side effects. Oral preparations have a 30-minute onset of action, making them impractical for the control of acute asthma.
Is it better to give albuterol through an MDI or through a nebulizer? The Cochrane Collaboration reviewed 16 controlled trials of children older than 2 years and compared delivery by an MDI with holding chamber with that by wet nebulization in the emergency department for treatment of acute, non-life-threatening asthma.5 The method of delivery did not affect the rate of hospitalization. Compared with that of the nebulizer, use of the MDI was associated with a substantially shorter stay in the emergency department and a substantially lower pulse rate. The Cochrane group concluded that an MDI with holding chamber is at least equivalent to nebulizer delivery in the treatment of acute, non-life-threatening exacerbations. It also offers the advantages of lower cost, shorter treatment time, and greater portability.
Mast cell stabilizers
Cromolyn sodium and nedocromil sodium are mast cell stabilizers used to control inflammation in asthma and to prevent exercise-induced bronchospasm. These agents inhibit the degranulation of mast cells, which prevents the release of inflammatory mediators.
Both agents are more effective than placebo in the prophylactic treatment of asthma5 and of exercise-induced bronchospasm.6 Cromolyn and nedocromil are equivalent to low-dose inhaled steroids in patients who have mild to moderate asthma7,8,9 but are not as effective as mid- to high-dose inhaled steroids.10 Therefore, they are indicated for use as monotherapy only for those with mild persistent asthma.3
Mast cell stabilizers have few side effects. Significant adverse drug reactions occur in only 1 of 10,000 patients.11 Because of this excellent side effect profile, they are recommended as first-line agents in children with mild persistent asthma, especially those aged 5 years and younger. Compliance may be difficult, however, because both medications are administered 2 to 4 times a day. Nedocromil has a bitter taste that can be lessened with the use of an MDI holding chamber.
Inhaled corticosteroids
Inhaled corticosteroids are indicated for the long-term control of mild persistent to severe persistent asthma. They are the most effective agents available for the control of inflammation aside from oral steroids.11 Inhaled corticosteroids are considered by the NHLBI as first-line therapy for mild to severe persistent asthma in children and adults.3 Nevertheless, they continue to be underused by patients and providers. A retrospective study of 1,025 asthmatic children aged 2 months to 16 years found that only 26% of children with moderate or severe asthma and 32% of children with 2 or more hospitalizations per year used a controller medicine during the past month, which indicates that most patients are suboptimally controlled and are undertreated.12
Inhaled corticosteroids control inflammation by decreasing proinflammatory cytokine levels, inflammatory cell recruitment, vascular permeability, and mucous production.11 This results in decreased bronchial hyperreactivity, and it prevents irreversible impairment of lung function. Because inhaled steroids prevent lung damage, their use is recommended as first-line therapy in children and infants diagnosed with asthma.3
The efficacy of inhaled steroids depends on many factors, such as topical potency, receptor binding affinity, half-life, and bioavailability. Studies to date have not compared all available medications and have often used animal models that have questionable correlation to humans to assess potency. The NHLBI has synthesized this information into dosing guidelines with equivalent low, medium, and high doses for each available inhaled steroid for adults and children (tables 4 and table 5).3
Table 4.
Comparative daily dosages for inhaled corticosteroids to treat asthma in adults and adolescents*
| Drug | Low dose, μg | Medium dose, μg | High dose, μg |
|---|---|---|---|
| Beclomethasone dipropionate | 168-504 | 504-840 | >840 |
| 42 μg per puff | 4-12 puffs | 12-20 puffs | >20 puffs |
| 84 μg per puff | 2-6 puffs | 6-10 puffs | >10 puffs |
| Budesonide (inhaled) | 200-400 | 400-600 | >600 |
| 200 μg per dose | 1-2 inhalations | 2-3 inhalations | >3 inhalations |
| Flunisolide | 500-1,000 | 1,000-2,000 | >2,000 |
| 250 μg per puff | 2-4 puffs | 4-8 puffs | >8 puffs |
| Fluticasone† | 88-264 | 264-660 | >660 |
| MDI: 44 μg per puff | 2-6 puffs | — | — |
| MDI: 110 μg per puff | 2 puffs | 2-6 puffs | >6 puffs |
| MDI: 220 μg per puff | — | — | >3 puffs |
| DPI: 50 μg per dose | 2-6 inhalations | — | — |
| DPI: 100 μg per dose | — | 3-6 inhalations | >6 inhalations |
| DPI: 250 μg per dose | — | — | >2 inhalations |
| — | (250 μg) | ||
| Triamcinolone aceteonide | 400-1,000 | 1,000-2,000 | >2,000 |
| 100 μg per puff | 4-10 puffs | 10-20 puffs | >20 puffs |
| MDI = metered-dose inhaler; DPI = dry-powder inhaler. | |||
From the National Asthma Education and Prevention Program.3
Dash (—) indicates not applicable.
Table 5.
Comparative daily dosages of inhaled corticosteroids for the treatment of asthma in children*
| Drug | Low dose, μg | Medium dose, μg | High dose μg |
|---|---|---|---|
| Beclomethasone dipropionate | 84-336 | 336-672 | >672 |
| 42 μg per puff | 2-8 puffs | 8-16 puffs | >16 puffs |
| 84 μg per puff | 1-4 puffs | 4-8 puffs | >8 puffs |
| Budesonide (inhaled)† | 100-200 | 200-400 | >400 |
| 200 μg per dose | — | 1-2 inhalations | >2 inhalations |
| Flunisolide | 500-750 | 1,000-1,250 | >1,250 |
| 250 μg per puff | 2-3 puffs | 4-5 puffs | >5 puffs |
| Fluticasone† | 88-176 | 176-440 | >440 |
| MDI: 44 μg | 2-4 puffs | 4-10 puffs | — |
| MDI: 110 μg | — | 2-4 puffs | >4 puffs |
| MDI: 220 μg | — | — | >2 puffs |
| DPI: 50 μg per dose | 2-4 inhalations | — | — |
| DPI: 100 μg per dose | — | 2-4 inhalations | >4 inhalations |
| DPI: 250 μg per dose | — | — | >2 inhalations |
| Triamcinolone acetonide | 400-800 | 800-1,200 | >1,200 |
| 100 μg per puff | 4-8 puffs | 8-12 puffs | >12 puffs |
| MDI = metered-dose inhaler; DPI = dry-powder inhaler. | |||
From the National Asthma Education and Prevention Program.3
Dash (—) indicates not applicable.
Patients' asthma should be controlled with the lowest effective dose of inhaled steroid to minimize adverse effects. Exogenous steroids can result in decreased cortisol production and eventual atrophy of the adrenal cortex.13 A meta-analysis of the effects of inhaled steroids on urinary and morning cortisol levels found that administering fluticasone propionate, 1.0 mg a day, caused cortisol suppression equivalent to 10 mg of oral prednisone,14 which shows the need to minimize steroid dosing.
Whether inhaled steroids suppress a child's growth is controversial. Both uncontrolled asthma and the use of inhaled steroids can impair growth. Short-term studies of growth velocity have shown conflicting results. Two long-term studies found no difference between children with asthma and age-matched controls.15, 16 A recent long-term study of 211 children who were taking budesonide found that patients reached target adult height to the same extent as controls and found no significant correlation between duration or cumulative dose and adult height.17 Therefore, the beneficial effect on growth of controlling asthma appears to outweigh any detrimental effects of the medicines.14
Inhaled steroids may affect bone turnover, which could cause decreased bone mineral density (BMD) and osteoporosis. Studies to show a change in fracture rate in children or adults have not been done. A study of 157 asthmatic children who took budesonide for 3 to 6 years found no difference in the BMD compared with controls who did not have asthma.14 Studies of adults have shown decreased BMD in postmenopausal women only,14 and investigators recommend that patients with strong risk factors for osteoporosis who are treated with doses of beclomethasone dipropionate, budesonide, or fluticasone greater than 1.0 mg per day receive calcium supplementation.18
Inhaled steroids may increase the risk of posterior subcapsular cataracts, open-angle glaucoma, and ocular hypertension. A cross-sectional study of 370 adult patients who used inhaled steroids found a 2-fold increase in the risk of cataracts linked to the cumulative dose.19 Periodic eye examinations are recommended.14
Long-acting β-agonists: salmeterol
Salmeterol xinafoate is a long-acting β2-adrenergic agonist indicated for the maintenance treatment of asthma and of exercise-induced bronchospasm. Because it acts in 20 minutes, and its peak efficacy occurs 1 to 4 hours after administration, salmeterol is not indicated for the relief of acute asthma attacks. Patients taking salmeterol should be instructed to continue albuterol for acute exacerbations.
Salmeterol is not recommended for use as monotherapy. The mainstay of therapy for mild persistent asthma or worse is an anti-inflammatory medicine, not salmeterol. For example, Simons randomly allocated 241 patients aged 6 to 14 years with asthma to receive beclomethasone, salmeterol, or placebo during 1 year.20 The use of beclomethasone, but not salmeterol, was associated with decreased bronchial hyperreactivity, rescue albuterol use, and acute asthmatic exacerbations.
The NHLBI recommends considering the use of salmeterol for patients whose symptoms are uncontrolled with standard doses of anti-inflammatory medication.3 Salmeterol can provide additional symptom control with inhaled steroids before stepping up to the use of medium-or high-dose steroids.21 It is often used as an adjunct in patients with nocturnal symptoms because of its 12-hour duration of action. In a 12-week study of patients older than 12 years with moderate persistent asthma who used inhaled steroids, salmeterol use was associated with a substantial increase in forced expiratory volume in 1 second (FEV1), peak expiratory flow (PEF), and the percentage of nights without awakening, illustrating its effectiveness as an adjunct to anti-inflammatory medicines.22
Theophylline
Theophylline is indicated to relieve and to prevent symptoms of asthma. It causes mild bronchodilation, decreases vascular permeability, increases mucociliary clearance, and increases contractility of the diaphragm. It may also have anti-inflammatory activity, such as inhibiting the release of leukotrienes. Theophylline is rarely used because of its narrow therapeutic index and the high risk of side effects (see box).
Theophylline is no longer routinely used to control asthma exacerbations. A study of patients with acute exacerbations who went to emergency departments found no benefit from adding theophylline to regimens of albuterol and corticosteroids.23 Patients in respiratory failure were excluded from this trial, and theophylline may have a place in treating such patients.
As with salmeterol, the NHLBI recommends using theophylline only as an adjunct to steroids.3 Theophylline decreases nocturnal symptoms, improves exercise tolerance, and decreases cough and wheezing when given with beclomethasone.24
Table 6.
| Theophylline: a narrow therapeutic index |
|---|
| Therapeutic range: 10-20 mg/mL |
| At concentrations double the therapeutic range, it can cause seizures, permanent neurologic deficit, tachycardia, arrhythmias, and death23 |
| At concentrations greater than 20 mg/mL, theophylline commonly causes nausea, vomiting, diarrhea, and headache |
| Concentrations must be closely monitored because of the large variability in the metabolism of the drug |
| Elimination of the drug depends on age, smoking status, and drug interactions |
Several studies have compared the use of salmeterol with that of theophylline.25,26,27 A study of 484 adults and adolescents with moderate asthma found salmeterol significantly more effective than theophylline in improving morning PEF and in decreasing asthma symptoms, night-time awakenings, and albuterol use.25 Two small studies found no difference in quality of sleep with the use of either medicine.26,27
Leukotriene inhibitors
Three leukotriene inhibitors—montelukast, zafirlukast, and zileuton—are approved for the treatment of mild persistent to severe persistent asthma. Leukotrienes are formed as part of the arachidonic acid pathway that leads to inflammation. The inhibition of leukotrienes controls inflammation by decreasing microvascular permeability, edema, and bronchoconstriction.
Leukotriene inhibitors are generally well tolerated. The most significant and controversial side effect reported has been Churg-Strauss syndrome (allergic angiitis and granulomatosis) in association with tapering the steroid dosage. It is unclear if the syndrome is the result of the steroid taper or of the leukotriene inhibitor.28 Zileuton use can impair liver function. The Food and Drug Administration recommends checking liver function test results at base-line, monthly for 3 months, and then every 2 to 3 months for the first year. Impaired liver function has not been reported with the use of montelukast or zafirlukast.
At the time of the completion of the NHLBI guidelines, the place of leukotriene inhibitors for monotherapy or as an adjunct had not been determined; however, several recent studies have helped to clarify their role.29,30,31 Leukotriene inhibitors have been compared with low-dose inhaled steroids for the treatment of mild persistent asthma. A study of 895 patients aged 15 to 85 years randomly allocated to receive montelukast or beclomethasone found both agents to be more effective than placebo. Although montelukast had a faster onset of action, beclomethasone was significantly more effective in improving FEV1, PEF, and quality of life and in decreasing the number of asthma attacks. Therefore, leukotriene inhibitors are not as effective as low-dose inhaled steroids.30
Like salmeterol or theophylline, leukotriene inhibitors have been studied as adjunctive therapy in patients with persistent asthma who already use inhaled steroids. A study of 642 adult patients found the use of beclomethasone plus montelukast to be superior to that of beclomethasone or montelukast alone.28 A study comparing the use of zafirlukast with that of salmeterol as adjunctive therapy with inhaled steroids in adults and adolescents found that the use of salmeterol resulted in significantly better function and symptom scores than that of zafirlukast.31 Salmeterol may be more effective than leukotriene inhibitors as an adjunct, although more studies are needed. No studies have been published that compare the use of leukotriene inhibitors with that of theophylline.
Leukotriene inhibitors can be used to inhibit exercise-induced bronchospasm. These drugs have been found to be superior to salmeterol and equivalent to cromolyn sodium for this condition.28
IMPROVING COMPLIANCE
Patients often find it difficult to comply with complicated dosing regimens that involve several inhalers with different uses. Adherence can be promoted by encouraging patients to become participants in the health care process. Asthma action plans or care plans encourage participation by fostering a decision-making role. For example, patients can be classified into “zones” based on their symptoms and peak flow values. The zones are arranged like a stoplight, with the green zone indicating ideal asthma control, yellow indicating caution, and red indicating the need to contact a provider. Patients are given a written plan that describes which medicines should be given at what frequency in each zone. Asthma action plans eliminate confusion and decrease the number of hospitalizations, emergency department visits, and unscheduled clinic visits.32
It is important to assess the patient's technique with an MDI and holding chamber at each visit. Patients aged 6 years and younger can use a tidal-breathing technique with a holding chamber and mask, and patients older than 6 years can use the adult inhalation technique with a holding chamber. The use of a holding chamber reduces oropharyngeal deposition of medication and increases delivery to the lungs.33
CONCLUSIONS
Prompt aggressive treatment with anti-inflammatory medicines as first-line therapy in mild persistent to severe persistent asthma improves asthma control and prevents lung damage. Recent studies of adjunctive medicines provide more options for improved patient care. New developments in asthma education allow patients to become partners with providers in the health care process.
Summary points
Early and aggressive treatment with anti-inflammatory medicine is the key to asthma management in children
If albuterol use exceeds twice a week, anti-inflammatory medication is indicated
Albuterol administered by a metered-dose inhaler with holding chamber is as effective as nebulized albuterol in patients with acute non-life-threatening asthma attacks
Salmeterol xinafoate, theophylline, and antileukotrienes provide additional symptom control when used with anti-inflammatory drugs
Salmeterol and theophylline are not recommended for use as monotherapy
Patient adherence can be fostered with asthma action plans, and the use of holding chambers can improve medicine delivery
Figure 1.
On Asthma Awareness Day, a young girl shows her inhaler technique to Olympic medallist Jackie Joyner-Kersee
[John Harrington, HO/AP]
Figure 2.
A is for Asthma: a Sesame Street video designed to raise awareness of pediatric asthma
Children's Television Workshop, Richard Termine/AP
Competing interests: None declared
Author: Heidi Kalister is a clinical pharmacist at Harborview Medical Center in Seattle; she works with children with asthma in the Children's and Teens' Clinic.
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