Albuterol sulfate is used orally or by oral inhalation for the symptomatic management of bronchospasm in patients with reversible, obstructive airway disease and by oral inhalation for the prevention of exercise-induced bronchospasm. Levalbuterol hydrochloride or levalbuterol tartrate is used by oral inhalation for the symptomatic management or prevention of bronchospasm in patients with reversible, obstructive airway disease. Albuterol sulfate in fixed combination with ipratropium bromide is used by oral inhalation for the symptomatic management of bronchospasm associated with chronic obstructive pulmonary disease (COPD) in patients who continue to have evidence of bronchospasm despite the regular use of an orally inhaled bronchodilator and who require a second bronchodilator.
Clinical studies in adults and children 4 years of age or older indicate that albuterol sulfate inhalation aerosol with a hydrofluoroalkane (HFA) propellant (e.g., Proventil HFA, Ventolin HFA) has bronchodilator efficacy similar to that of albuterol inhalation aerosol with chlorofluorocarbons (no longer commercially available in the US). In one short-term (3 weeks' duration), randomized, double-blind, placebo-controlled study in children 4 to 11 years of age with asthma, patients receiving albuterol sulfate HFA inhalation aerosol (i.e., ProAir HFA) at dosages of 180 mcg 4 times daily showed greater improvement in FEV1 compared with baseline than did patients receiving placebo. In this study, 42% of children receiving albuterol sulfate HFA inhalation aerosol achieved a 15% increase in FEV1 within 30 minutes postdose on the first day of the trial.
Albuterol solution for nebulization is used for the symptomatic treatment and control of acute, potentially recurrent bronchospasm in patients with reversible obstructive airway disease, including those with bronchial asthma, chronic bronchitis, pulmonary emphysema, and cystic fibrosis. Administration of β-adrenergic agonist bronchodilators via nebulization generally is reserved for patients with severe disease who do not respond adequately to more conventional therapy and for patients (e.g., children) who find it difficult or are unable to optimally inhale the drug orally via an inhaler. In clinical studies of orally inhaled albuterol sulfate via nebulization in asthmatic children aged 3 years or older, improvement in indices of pulmonary function (FEV1 or PEFR) occurred within 2-20 minutes following single doses of nebulized drug. Following oral inhalation of nebulized albuterol sulfate (0.1 mg/kg or higher), clinically important increases in FEV1 (as measured by a 15% increase compared with baseline) have been observed for up to 6 hours in children 5-11 years of age. In a short-term (4-weeks' duration), randomized, double-blind, placebo-controlled study in children 6-12 years of age with mild to moderate asthma (mean baseline FEV1 60-70% of predicted values) who received albuterol 0.63 or 1.25 mg 3 times daily via nebulization with or without corticosteroids, the mean percent change in the area under the FEV1-time curve over 6 hours with albuterol exceeded that produced by placebo. The mean time to peak effect (as determined by increase in FEV1) with both doses was approximately 30-60 minutes postdose; no diminution of effect was noted during the 4-week period of observation.
Levalbuterol hydrochloride solution for nebulization and levalbuterol tartrate inhalation aerosol are used as bronchodilators for the symptomatic management and prevention of bronchospasm in patients with reversible obstructive airway disease. Current evidence suggests that most, if not all, of the bronchodilatory activity of albuterol is attributable to levalbuterol (R-albuterol) and that the S-enantiomer may potentially detract from the efficacy of racemic albuterol.(See Pharmacology.)
Safety and efficacy of levalbuterol tartrate with an HFA propellant via a metered-dose inhaler for the treatment of asthma have been established in 3 randomized, double-blind, placebo- and active-controlled studies of 4-8 weeks' duration in adults and children 4 years of age or older. Levalbuterol (90 mcg) and racemic albuterol with an HFA propellant (180 mcg) were more effective than placebo in improving lung function (defined as mean peak percent change from baseline in FEV1).
In a small, placebo-controlled, dose-ranging study in adults with mild to moderate asthma receiving single doses of orally inhaled levalbuterol (0.31, 0.63, or 1.25 mg) or racemic albuterol (2.5 mg) via nebulization, the bronchodilator response to the highest dosage of levalbuterol (1.25 mg) was clinically comparable to that with albuterol 2.5 mg over the 6-hour evaluation period, although the period during which the increase in FEV1 exceeded 15% compared with baseline was slightly more prolonged with levalbuterol. Adverse systemic β-adrenergic effects were observed with both treatments and generally were dose-related for R-albuterol, although the 1.25-mg dosage of levalbuterol was associated with a slightly greater incidence of such adverse effects than the 2.5-mg dosage of albuterol.
In a short-term (4-weeks' duration), placebo-controlled study in adults and adolescents with moderate to severe asthma (mean baseline FEV1 60% of predicted) who received levalbuterol 0.63 or 1.25 mg 3 times daily or albuterol 1.25 or 2.5 mg 3 times daily via nebulization, the mean peak change in FEV1 with levalbuterol (R-albuterol) exceeded that produced by equivalent dosages of the drug given as racemic albuterol (50:50 mixture of R- and S-albuterol). This improvement in FEV1 in all patients receiving levalbuterol exceeded that for the combined albuterol group after the first dose (day 1) but not at the end (day 29) of the study. Improvement in FEV1 was greatest and of longest duration with the levalbuterol 1.25-mg dosage regimen on days 1 and 29, while efficacy of the levalbuterol 0.63-mg and albuterol 2.5-mg regimens was similar at all time points measured. All active treatments were associated with improvement in FEV1 compared with placebo, and adverse effects of levalbuterol and albuterol were similar.
In a short-term (3-weeks' duration), randomized, double-blind, placebo-controlled study in children (6-11 years of age) with mild to moderate asthma (mean baseline FEV1 73% of predicted) who received levalbuterol (0.31 or 0.63 mg 3 times daily) or racemic albuterol (1.25 or 2.5 mg 3 times daily) via nebulization in addition to existing therapy (e.g., inhaled corticosteroids), the mean peak change in FEV1 with levalbuterol (R-albuterol) was similar to that produced by albuterol. All active treatments were associated with improvement in FEV1 compared with placebo, and adverse effects of levalbuterol were less than that associated with albuterol.
Considerations in Initiating Antiasthma Therapy
In the current stepped-care approach to antiasthmatic drug therapy, asthma is classified according to severity upon initial presentation (intermittent asthma or mild, moderate, or severe persistent asthma) and also by response to treatment (i.e., asthma control). While classification of asthma severity is useful for determining initial treatment, disease severity may vary over time and with treatment; therefore, after therapy is initiated, periodic assessment of asthma control is emphasized for guiding treatment decisions. Current asthma management guidelines state that initial therapy for asthma should correspond to disease severity, with subsequent monitoring and adjustments in therapy to achieve and maintain control of asthma according to the goals of treatment. Asthma therapy is aimed at achieving and maintaining control of asthma by reducing ongoing impairment (e.g., prevention of chronic and troublesome symptoms, reducing use of reliever drugs, maintaining normal or near-normal lung function and activity levels) and risk of future events (e.g., exacerbations requiring systemic corticosteroids, treatment-related adverse effects). These 2 components of asthma control (i.e., current impairment and future risk) may respond differently to treatment.
The National Asthma Education and Prevention Program (NAEPP) classifies the levels of asthma control as well controlled, not well controlled, or very poorly controlled. In the stepped-care approach, the treatment step selected for asthma control in patients already receiving asthma therapy is based on the patient's current treatment and level of asthma control. Stepwise therapy is meant to assist, not replace, the clinical decision-making process in selecting therapy for individual patients. Once initiated, treatment is adjusted continuously according to changes in asthma control. Patients should be monitored every 2-6 weeks following initiation of therapy to ensure that asthma control is achieved. If asthma symptoms are not controlled with the current treatment regimen, treatment is stepped up until control is achieved. If an alternative treatment was used and produced an inadequate response, the preferred treatment should be used before stepping up to the next level of therapy. Regular monitoring at 1- to 6-month intervals, depending on the level of control, is recommended to ensure that control of asthma is maintained and that appropriate adjustments in therapy are made. When control has been maintained for at least 3 months, treatment intensity may be stepped down to find the lowest dosage and/or number of drugs required to maintain asthma control, with continued follow-up at 3-month intervals.
Drugs for asthma may be categorized as relievers (e.g., bronchodilators taken as needed for acute symptoms) or controllers (principally inhaled corticosteroids or other anti-inflammatory agents taken regularly to achieve long-term control of asthma).
A reliever drug such as a selective short-acting inhaled β2-adrenergic agonist (e.g., albuterol, levalbuterol, pirbuterol), is recommended on an as-needed basis to control occasional acute symptoms (e.g., cough, wheezing, dyspnea) of short duration; such use of an inhaled short-acting β2-agonist alone generally is sufficient as initial treatment for newly diagnosed patients whose asthma severity is initially classified as intermittent (e.g., patients with daytime symptoms of asthma not more than twice weekly and nocturnal symptoms not more than twice a month). Most experts consider short-acting inhaled β2-adrenergic agonists to be drugs of choice for treating acute asthma symptoms and exacerbations and for preventing exercise-induced bronchospasm. Alternatives to short-acting inhaled β2-agonists recommended by some clinicians for relief of acute asthma symptoms include an inhaled anticholinergic agent (e.g., ipratropium), a short-acting oral β2-agonist, or a short-acting theophylline (provided extended-release theophylline is not already used), but these alternatives have a slower onset of action and/or a greater risk of adverse effects. Oral β2-adrenergic agonist therapy is suggested for use principally in patients unable to use inhaled bronchodilators (e.g., young children). Other experts do not recommend oral β2-agonists for relief of acute asthma symptoms. Use of short-acting inhaled β2-agonists in asymptomatic asthma should be limited to pretreatment prior to exercise and, in intermittent asthma, should be limited to providing relief as symptoms develop; some clinicians state that patients requiring symptomatic relief more than twice weekly or repeatedly over 1 or 2 days should be evaluated for possible initiation of long-term controller therapy.
Mild Persistent Asthma
When control of symptoms deteriorates in patients with intermittent asthma and symptoms become persistent (e.g., daytime symptoms of asthma more than twice weekly but less than once daily, and nocturnal symptoms of asthma 3-4 times per month), current asthma management guidelines and most clinicians recommend initiation of a controller drug such as an anti-inflammatory agent, preferably a low-dose orally inhaled corticosteroid, (e.g., 88-264, 88-176, or 176 mcg of fluticasone propionate [or its equivalent] daily via a metered-dose inhaler in adolescents and adults, children 5-11 years of age, or children 4 years of age or younger, respectively) as first-line therapy for persistent asthma, supplemented by as-needed use of a short-acting, inhaled β2-agonist. Alternatives to low-dose inhaled corticosteroids for mild persistent asthma include certain leukotriene modifiers (i.e., montelukast, zafirlukast), extended-release theophylline, or mast-cell stabilizers (i.e., cromolyn, nedocromil [preparations for oral inhalation no longer commercially available in the US]), but these therapies are less effective and generally not preferred as initial therapy. Some experts recommend that long-term control therapy be considered in infants and children 4 years of age or younger who have identifiable risk factors for asthma (e.g., parental history of asthma, clinician-diagnosed atopic dermatitis, sensitization to aeroallergens, or 2 of the following conditions: sensitization to foods, peripheral blood eosinophilia exceeding 4%, or wheezing unrelated to colds) and who in the previous year have had 4 or more episodes of wheezing that lasted more than 1 day and symptoms that affected sleep. Low-dose inhaled corticosteroids also are recommended as the preferred initial therapy in such children. Cromolyn sodium is suggested (based on extrapolation of data from studies in older children) or montelukast is recommended by some experts as an alternative, but not preferred, therapy in children 4 years of age or younger with mild persistent asthma. Other experts do not consider mast-cell stabilizers or extended-release theophylline to be acceptable alternatives to inhaled corticosteroids for routine use as initial long-term therapy in such patients.
Moderate Persistent Asthma
According to current asthma management guidelines, therapy with a long-acting inhaled β2-agonist such as salmeterol or formoterol generally is recommended in adults and adolescents who have moderate persistent asthma and daily asthmatic symptoms that are inadequately controlled following addition of low-dose inhaled corticosteroids to as-needed inhaled β2-agonist treatment. However, the NAEPP recommends that the beneficial effects of long-acting inhaled β2-agonists should be weighed carefully against the increased risk (although uncommon) of severe asthma exacerbations and asthma-related deaths associated with daily use of such agents. Current asthma management guidelines also state that an alternative, but equally preferred option for management of moderate persistent asthma that is not adequately controlled with a low dosage of inhaled corticosteroid is to increase the maintenance dosage to a medium dosage (e.g., exceeding 264 but not more than 440 mcg of fluticasone propionate [or its equivalent] daily via a metered-dose inhaler in adults and adolescents). Alternative less-effective therapies that may be added to a low dosage of an inhaled corticosteroid include oral extended-release theophylline or certain leukotriene modifiers (i.e., montelukast, zafirlukast).
Limited data are available in infants and children 11 years of age or younger with moderate persistent asthma, and recommendations of care are based on expert opinion and extrapolation from studies in adults. According to current asthma management guidelines, a long-acting inhaled β2-agonist (e.g., salmeterol, formoterol), a leukotriene modifier (i.e., montelukast, zafirlukast), or extended-release theophylline (with appropriate monitoring) may be added to low-dose inhaled corticosteroid therapy in children 5-11 years of age. Because comparative data establishing relative efficacy of these agents in this age group are lacking, there is no clearly preferred agent for use as adjunctive therapy with a low-dose inhaled corticosteroid for treatment of asthma in these children. In children 5-11 years of age with moderate persistent asthma that is not controlled with a low dosage of an inhaled corticosteroid, another preferred option according to current asthma management guidelines is to increase the maintenance dosage of the inhaled corticosteroid to a medium dosage (e.g., exceeding 176 but not more than 352 mcg of fluticasone propionate [or its equivalent] daily via a metered-dose inhaler). In infants and children 4 years of age or younger with moderate persistent asthma that is not controlled by a low dosage of an inhaled corticosteroid, the only preferred option is to increase the maintenance dosage of the inhaled corticosteroid to a medium dosage (e.g., exceeding 176 but not more than 352 mcg of fluticasone propionate [or its equivalent] daily via a metered-dose inhaler).
Severe Persistent Asthma
Maintenance therapy with an inhaled corticosteroid at medium dosages or high dosages (e.g., exceeding 440 mcg of fluticasone propionate in adults and adolescents or 352 mcg of the drug in children 5-11 years of age [or its equivalent] daily via a metered-dose inhaler) and adjunctive therapy with a long-acting inhaled β2-agonist is the preferred treatment according to current asthma management guidelines in adults and children 5 years of age or older with severe persistent asthma (i.e., continuous daytime asthma symptoms, nighttime symptoms 7 times per week). Such recommendations in children 5-11 years of age are based on expert opinion and extrapolation from studies in older children and adults. Alternatives to a long-acting inhaled β2-agonist for severe persistent asthma in adults and children 5 years of age or older receiving medium-dose inhaled corticosteroids include extended-release theophylline or certain leukotriene modifiers (i.e., montelukast, zafirlukast), but these therapies are generally not preferred. Omalizumab may be considered in adults and adolescents with severe asthma with an allergic component who are inadequately controlled with high-dose inhaled corticosteroids and a long-acting β2-agonist. In infants and children 4 years of age or younger with severe asthma, maintenance therapy with an inhaled corticosteroid at medium or high dosages (e.g., exceeding 352 mcg of fluticasone propionate [or its equivalent] daily via a metered-dose inhaler) and adjunctive therapy with either a long-acting inhaled β2-agonist or montelukast is the only preferred treatment according to current asthma management guidelines. Recommendations for care of infants and children with severe asthma are based on expert opinion and extrapolation from studies in adolescents and adults.
Poorly Controlled Asthma
If asthma symptoms in adults and children 5 years of age or older with moderate to severe asthma are very poorly controlled (i.e., at least 2 exacerbations per year requiring oral corticosteroids) with low-to-high maintenance dosages of an inhaled corticosteroid and a long-acting inhaled β2-agonist bronchodilator, a short course (3-10 days) of an oral corticosteroid may be added to gain prompt control of asthma. In infants and children 4 years of age or younger with moderate to severe asthma who are very poorly controlled (more than 3 exacerbations per year requiring oral corticosteroids) with medium to high maintenance dosages of an inhaled corticosteroid with or without adjunctive therapy (i.e., a long-acting inhaled β2-agonist, montelukast), a short course (3-10 days) of an oral corticosteroid may be added to gain prompt control of asthma.
While clinical efficacy of oral corticosteroids as add-on therapy in adults and children 5 years of age or older with severe asthma who are inadequately controlled with a high-dose inhaled corticosteroid, intermittent oral corticosteroid therapy, and a long-acting inhaled β2-agonist bronchodilator has not been established in randomized controlled studies, some experts suggest regular use of oral corticosteroids in such patients, based on consensus and clinical experience. Similarly, some experts, based on consensus and clinical experience, suggest regular use of oral corticosteroid therapy in infants and children 4 years of age or younger with severe asthma who are not controlled with a high-dose inhaled corticosteroid and either a long-acting inhaled β2-agonist or montelukast and intermittent oral corticosteroid therapy. However, other experts do not consider regular use of oral corticosteroid therapy to be appropriate therapy in children with severely uncontrolled asthma.
When asthma symptoms at any stage are not controlled with maintenance therapy (e.g., inhaled corticosteroids) plus supplemental short-acting inhaled β2-agonist bronchodilator therapy as needed (e.g., if there is a need to increase the dose or frequency of administration of the short-acting sympathomimetic agent), prompt reevaluation is required to adjust dosage of the maintenance regimen or institute an alternative maintenance regimen.
Home Management of Acute Asthma Exacerbations
For acute exacerbations of asthma, initial home treatment consists of use of an inhaled short-acting β2-agonist (no more than 2 doses via a metered-dose inhaler with 2-6 inhalations per dose or via nebulization every 20 minutes). Patients who have exacerbations of less severity may require a reduced dosage of a short-acting β2-agonist. If response is good (peak expiratory flow [PEF] returns to at least 80% of predicted value or personal best and response is maintained for 3-4 hours), therapy with a short-acting β2-agonist should be continued every 3-4 hours for 24-48 hours, and a short course of an oral corticosteroid may be considered. If response is incomplete (PEF 50-79% of predicted value or personal best), therapy with an inhaled short-acting β2-agonist should be continued, and an oral corticosteroid should be added. If patients have a poor response to bronchodilator therapy (PEF less than 50% of predicted value or personal best), administration of an inhaled short-acting β2-agonist should be repeated immediately, and an oral corticosteroid should be added.
For management of exacerbations due to viral respiratory infections, a short-acting inhaled β2-agonist every 4-6 hours for 24 hours (longer therapy requires consultation with a clinician) in patients with mild symptoms may be sufficient to control symptoms and improve lung function. If viral infection-associated exacerbations occur more frequently than every 6 weeks, use of long-term control therapy should be considered. If a viral respiratory infection provokes moderate to severe exacerbations, a short course of an oral corticosteroid should be considered. For those with a history of severe exacerbations associated with viral infections, initiation of oral corticosteroids should be considered at the first sign of infection.
Prehospital Management of Acute Asthma Exacerbations
Should the response to home-initiated drug therapy be incomplete (PEF 50-79% of predicted value or personal best) or poor (PEF less than 50% of predicted value or personal best) after short-acting β2-agonist therapy, the patient should seek medical attention urgently (same day if response is incomplete) or proceed immediately to the emergency department of a hospital (if response is poor). Orally inhaled, selective short-acting β2-adrenergic agonists (i.e., albuterol, levalbuterol, pirbuterol) currently are recommended by an expert panel of NAEPP for prehospital management of asthma exacerbations (e.g., in emergency medicine facilities and/or ambulances). A short-acting β2-agonist should be administered via metered-dose inhaler or nebulization at a frequency not exceeding 3 doses every 20 minutes during the first hour, followed by 1 dose hourly thereafter; supplemental oxygen is also currently recommended. If a β2-adrenergic agonist and appropriate administration devices are not available for prehospital management, subcutaneous epinephrine or terbutaline should be given for severe exacerbations. During prolonged emergency transport, NAEPP recommends that other asthma therapies such as ipratropium bromide and oral corticosteroids should also be available for use. In patients with acute exacerbations of asthma, ipratropium generally has been reserved for use as an adjunct to other therapy, usually in combination with a β2-adrenergic agonist bronchodilator. Because of its delayed onset, ipratropium generally should not be used alone for the management of acute bronchospasm, particularly if a prompt response is required.
Management of Acute Asthma Exacerbations in Acute Care Setting
In the emergency department, orally inhaled, selective β2-adrenergic agonists via metered-dose inhaler or nebulization (not exceeding 3 doses every 20 minutes during the first hour) and supplemental oxygen currently also are recommended for asthma management in patients with mild to moderate acute exacerbations (FEV1 or PEF at least 40% of predicted or personal best). If response to a β2-adrenergic agonist in patients with mild to moderate asthma exacerbations is not immediate or if patients used oral corticosteroids as self-medication prior to hospitalization, systemic oral corticosteroids should be added to the regimen in the emergency department. Some clinicians suggest that adjunctive therapy with an inhaled anticholinergic bronchodilator (i.e., ipratropium) be considered in the emergency department in patients with moderate or severe exacerbations (PEF 60-80% or less than 60%, respectively, of predicted or personal best) of asthma who fail to respond adequately to β2-adrenergic agonists and corticosteroids. NAEPP recommends adjunctive therapy with ipratropium (via nebulization or a metered-dose inhaler) and oral corticosteroids in patients with severe asthma exacerbations (FEV1 or PEF less than 40% of predicted or personal best) in the emergency department who fail to respond adequately to short-acting, inhaled β2-agonists. If the episode is severe, 1 dose of a short-acting β2-agonist should be given and the patient should be assessed for potential hospitalization. Adjunctive therapy such as IV magnesium sulfate or a nebulization gas mixture of helium and oxygen (heliox) may be considered to decrease the likelihood of intubation, but intubation should not be delayed if the procedure is deemed necessary. In patients with impending respiratory failure, intubation and mechanical ventilation with 100% oxygen, a short-acting β2-adrenergic agonist in combination with ipratropium via nebulization given hourly or continuously, and an IV corticosteroid should be administered in the emergency department. In certain children with acute exacerbations of asthma, some evidence suggests that an orally inhaled β2-adrenergic agonist in conjunction with orally inhaled ipratropium (via nebulization) may be more effective than therapy with a β2-agonist alone. In one study in children with severe acute asthma, children with the most severe bronchospasm (defined as baseline FEV1 not exceeding 30% of predicted) who received repeated does of ipratropium in conjunction with albuterol were less likely to require hospitalization or additional bronchodilator therapy than children receiving albuterol alone. However, ipratropium does not appear to confer additional benefit in children once they have been hospitalized and treated with an intensive regimen including a nebulized β2-agonist and systemic corticosteroids. Based on such data in children, NAEPP recommends discontinuance of ipratropium upon hospitalization for severe asthma exacerbations for patients of all age groups.
A repeat assessment of response should be made in all patients after the initial hour of intensive conventional treatment in the emergency department. In patients who have a moderate asthma exacerbation (FEV1 or PEF of 40-69% of predicted or personal best) after the initial hour of intensive conventional treatment, an oral corticosteroid and an inhaled short-acting β2-agonist (once every hour) should be continued for 1-3 hours provided there is improvement; assessment of response and decision to hospitalize the patient should be made in less than 4 hours after admittance to the emergency department. For severe asthma exacerbations not responding to 1 hour of intensive conventional therapy, oxygen and oral corticosteroids should be continued and an inhaled short-acting β2-agonist and ipratropium should be administered via nebulization either continuously or hourly in the emergency department. Assessment of response in patients with severe asthma exacerbations should be repeated at 2 hours and discharge is appropriate in patients with a good response (FEV1 or PEF at least 70% of predicted value or personal best that is sustained for 60 minutes after last treatment, normal physical examination). If response is incomplete (FEV1 or PEF 40-69% of predicted or personal best and continuing mild to moderate symptoms), the decision to hospitalize the patient should be individualized.
Upon hospitalization, therapy with oxygen and an inhaled short-acting β2-agonist should be continued, and therapy with oral corticosteroids should be continued or intensified (switched from oral to IV). Adjunctive therapies (e.g., magnesium sulfate, heliox) could be considered in patients with an incomplete response to several hours of intensive therapy. Patients admitted to the hospital should be reassessed at regular intervals. Patients with a poor response to such hospitalization and interventions (FEV1 or PEF less than 40% of predicted or personal best) and those with an incomplete response after 6-12 hours of hospitalization should be admitted to an intensive care unit (ICU). Patients with a poor response to several hours of intensive therapy and patients with impending respiratory failure also should be admitted to an ICU. Upon ICU admission, therapy with ipratropium should be discontinued, but therapy with a short-acting β2-agonist, an IV corticosteroid, and possible adjunctive therapy should be continued. Discharge is appropriate in hospitalized patients with a good response. Upon discharge, treatment with a short-acting β2-agonist and an oral corticosteroid (3-10 days) should be continued and initiation of an inhaled corticosteroid should be considered.
Regular Use of Short-acting β2-Agonists
Concerns about the safety of regular use of short-acting inhaled β2-agonist bronchodilators for maintenance therapy of asthma have been raised by evidence from some studies suggesting increased morbidity and mortality in patients receiving long-term therapy with short-acting, inhaled β-agonists, particularly fenoterol (currently not commercially available in the US). Other studies in patients with mild or moderate asthma suggest that while regularly scheduled use of short-acting, inhaled β2-agonists may not cause harm, such use does not appear to have demonstrable advantages compared with intermittent use and does not adequately control asthmatic symptoms, peak flow variability, or airway hyperresponsiveness. Suggested mechanisms for detrimental effects of regularly scheduled, inhaled β-agonist therapy include down-regulation of β-adrenergic receptors (tolerance)(see Cautions: Precautions and Contraindications), increased responsiveness of airways to allergens and exercise, genetic changes in β2-agonist receptor gene, or increased airway accessibility to inhaled allergens, which may lead to increased airway inflammation and reactivity and worsening of asthma symptoms. The validity of the evidence from these studies has been criticized in terms of study design and/or interpretation of study findings and a causal relationship between inhaled β2-agonist therapy and asthma mortality has not been proven. Current asthma management guidelines and many clinicians recommend anti-inflammatory therapy with an inhaled corticosteroid as first-line therapy for long-term control in patients with persistent asthma, supplemented by as-needed use of a short-acting, inhaled β2-agonist. Regular, daily use of a short-acting, inhaled β2-agonist generally is not recommended, and increased chronic use of such β2-agonists more than twice weekly (excluding use for exercise-induced bronchospasm) or acute use (e.g., repeated use over more than 1-2 days) for asthma deterioration may indicate the need to initiate or increase long-term control therapy for asthma.
Orally inhaled albuterol sulfate administered via a metered-dose aerosol is used as a bronchodilator in the prevention of exercise-induced bronchospasm. Most experts consider short-acting inhaled β2-adrenergic agonists to be drugs of choice for prevention of exercise-induced bronchospasm. Treatment with a short-acting, inhaled β2-agonist immediately before vigorous activity or exercise may be helpful for 2-3 hours. If symptoms occur during usual exercise or play activities, a step up in long-term control therapy is warranted.
In clinical studies of orally inhaled albuterol aerosol for the prevention of exercise-induced bronchospasm in adults and children, administration of the drug 15 minutes prior to exercise prevented bronchospasm as evidenced by maintenance of FEV1 within 80% of baseline in most patients. In one placebo-controlled clinical study of orally inhaled albuterol sulfate aerosol (ProAir HFA) for the prevention of exercise-induced bronchospasm in adults and adolescents 12 years of age or older, administration of the drug 30 minutes prior to exercise prevented bronchospasm as evidenced by maintenance of FEV1 within 80% of baseline in most patients. In another study in adults, a similar prophylactic effect was observed despite repeated exercise challenge for up to 4 hours in the majority of patients and for 6 hours in approximately one third of such treated patients. In one study in asthmatic children, oral albuterol was as effective as orally inhaled albuterol, both in ability to produce bronchodilation and to prevent exercise-induced bronchospasm; however, oral albuterol's bronchodilating effect was delayed and its effect on some measures of pulmonary function (i.e., forced expiratory flow during the middle half of forced vital capacity [FEF25-75%], maximum expiratory flow after 75% forced vital capacity [V25]) following exercise was slightly less than that of orally inhaled albuterol.
Chronic Obstructive Pulmonary Disease
Regular use of selective, short-acting inhaled β2-adrenergic agonists in the management of chronic obstructive pulmonary disease (COPD), in contrast to that in asthma, does not appear to be detrimental. However, as long-acting β2-adrenergic agonists have become available for maintenance treatment of COPD, short-acting β2-adrenergic agonists are used by some clinicians mainly to relieve acute symptoms of COPD. Albuterol is used in combination with other bronchodilators or alone on an as-needed or regular (e.g., 4 times daily) basis for the management of mild to very severe COPD. Albuterol sulfate in fixed combination with ipratropium bromide is used as maintenance therapy of reversible bronchospasm associated with COPD in patients who continue to have evidence of bronchospasm despite regular use of an orally inhaled bronchodilator and who require a second bronchodilator. Therapy with anticholinergic and/or β-adrenergic agonist bronchodilators increases airflow and exercise tolerance and reduces dyspnea in patients with COPD.
In the stepped-care approach to drug therapy in patients with COPD, mild intermittent symptoms and minimal lung impairment (e.g., FEV1 at least 80% of predicted) can be treated with a short-acting, selective inhaled β2-agonist such as albuterol as needed for acute symptoms. Inhaled β2-adrenergic agonists are preferred over oral β2-agonist therapy for treatment of COPD. Oral β2-adrenergic agonists have a slower onset of action and an increased incidence of adverse effects compared with inhaled therapy; the role of oral β2-adrenergic agonists in treatment of COPD is limited.
In patients with moderate (e.g., FEV1 50-80% of predicted) COPD who have persistent symptoms despite as-needed therapy with ipratropium or a selective inhaled β2-agonist, maintenance treatment with a long-acting bronchodilator (e.g., formoterol, salmeterol, tiotropium) can be added and a short-acting, selective inhaled β2-agonist be used as needed for immediate symptom relief. Maintenance treatment with long-acting bronchodilators is recommended in such patients as this therapy is more effective and convenient than regular use of short-acting bronchodilators. For patients not responding adequately to treatment following addition of a long-acting bronchodilator, a combination of several long-acting bronchodilators such as tiotropium and a long-acting β-adrenergic agonist may be used.
Maintenance therapy (e.g., 4 times daily) with a short-acting, selective inhaled β2-agonist is not preferred but may be used in patients with persistent symptoms of COPD; such therapy should not exceed 6-12 inhalations daily. Current guidelines for the management of COPD state that low- to high-dose ipratropium (6-16 inhalations daily) can be added to therapy with a short-acting, selective inhaled β2-agonist in patients with mild to moderate persistent symptoms of COPD, with the frequency of inhalation therapy with either agent not to exceed 4 times daily; the high dosage of ipratropium included in some guidelines for COPD exceeds the manufacturer's maximum recommended dosage (12 inhalations). Combining bronchodilators from different classes and with differing durations of action may increase the degree of bronchodilation with a similar or lower frequency of adverse effects. In several randomized, double-blind clinical trials, albuterol sulfate and ipratropium bromide in fixed combination for oral inhalation produced greater improvement in pulmonary function (i.e., mean FEV1 compared with baseline) than either drug alone; the median duration of effect (as measured by FEV1) was 4-5 hours for the fixed combination compared with 4 hours for ipratropium bromide and 3 hours for albuterol sulfate. For additional information on the use of albuterol and ipratropium in fixed combination for patients with COPD,
For treatment of severe to very severe COPD (e.g., FEV1 30-50% of predicted or less, history of exacerbations), the addition of an inhaled corticosteroid to one or more long-acting bronchodilators given separately or in fixed combination may be needed. If symptoms are not adequately controlled with inhaled corticosteroids and a long-acting bronchodilator, or if limiting adverse effects occur, oral extended-release theophylline may be added or substituted.
Management of acute exacerbations of COPD at home is based initially on the same drugs used for management of the stable patient. A short-acting β2-adrenergic agonist is the preferred bronchodilator for treatment of acute exacerbations of COPD. If response to a short-acting β2-adrenergic agonist alone is inadequate, some clinicians recommend the addition of ipratropium. In a severe exacerbation (FEV1 less than 50% of predicted) treated at home, administration of these agents by nebulization or metered-dose inhalation with a spacer device may be used as needed for short-term therapy. For more severe exacerbations of COPD (e.g., FEV1 less than 50% of predicted), a short (e.g., 7-10 days) course of oral corticosteroids (e.g., equivalent to 30-40 mg of prednisone daily) can be added to bronchodilator therapy. If symptoms of COPD continue to deteriorate several hours after administration of oral corticosteroids (e.g., sudden development of resting dyspnea, cyanosis, peripheral edema, changes in mental status, inability to eat or sleep because of symptoms), the patient should be hospitalized. Following initiation of oxygen therapy in hospitalized patients, therapy with short-acting β2-adrenergic agonist and/or ipratropium (administered separately or in fixed combination) should be used for acute exacerbations of COPD, although the effectiveness of such combination therapy remains controversial. Oral corticosteroids are especially helpful within the first 72 hours of an acute exacerbation and should be initiated early in the management of the hospitalized patient. If patients cannot tolerate oral corticosteroids, IV corticosteroids should be initiated. If necessary for severe exacerbations, appropriate anti-infective therapy can be initiated if indicated (purulent exacerbations).
Orally inhaled albuterol has been used effectively to prevent or alleviate episodes of muscle paralysis in the treatment of some patients with hyperkalemic familial periodic paralysis.