The goal is rapid reversal of airflow obstruction by repetitive or continuous administration of inhaled β2-agonists, ensuring adequate oxygenation, and relieving inflammation.7,8,9,10 Figure 69-1 shows the National Asthma Education and Prevention Program Expert Panel ED treatment algorithm.10 The following categories of medications are used in the treatment of acute asthma: β-adrenergic agonists, anticholinergics, and glucocorticoids. Treatments for impending or actual respiratory arrest are discussed below in "Status Asthmaticus."
Management of asthma exacerbations: ED and hospital-based care. FEV1 = forced expiratory volume in 1 second; ICS = inhaled corticosteroid; MDI = metered-dose inhaler; PEFR = peak expiratory flow rate; SABA = short-acting β2-agonist; Sao2 = oxygen saturation by pulse oximetry. [Source: http://www.nhlbi.nih.gov/guidelines/asthma/asthgdln.pdf (National Heart, Lung, and Blood Institute; National Institutes of Health; U.S. Department of Health and Human Services: National Asthma Education and Prevention Program, Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma. Publication No. 08-4051. Bethesda, MD, National Institutes of Health, 2007.) Accessed November 18, 2014.]
β-Adrenergic agonists with rapid onset are the preferred initial rescue medication for acute bronchospasm (Table 69-5). Stimulation of β1-receptors increases rate and force of cardiac contraction and decreases small intestine motility and tone, whereas β2-adrenergic stimulation promotes bronchodilation, vasodilation, uterine relaxation, and skeletal muscle tremor.
TABLE 69-5β-Adrenergic, Anticholinergic, and Steroid Dosages of Drugs for Asthma ||Download (.pdf) TABLE 69-5 β-Adrenergic, Anticholinergic, and Steroid Dosages of Drugs for Asthma
|Medication ||Dose ||Comments |
|Inhaled β2-Agonists |
|Albuterol || || |
|Nebulizer solution (0.63 milligram/3 mL, 1.25 milligrams/3 mL, 2.5 milligrams/3 mL, 5.0 milligrams/mL) ||2.5–5 milligrams every 20 min for three doses, then 2.5–10 milligrams every 1–4 h, as needed, or 10–15 milligrams/h as continuous nebulization. ||Only selective β2-agonists are recommended. For optimal delivery, dilute aerosols to minimum of 3 mL at gas flow of 6–8 L/min. Use large-volume nebulizers for continuous administration. May mix with ipratropium nebulizer solution. |
|MDI (90 micrograms/puff) ||4–8 puffs every 20 min up to 4 h, then every 1–4 h as needed. ||In mild-to-moderate exacerbations, MDI plus valved holding chamber is as effective as nebulized therapy with appropriate administration technique and coaching by trained personnel. |
|Bitolterol || || |
|Nebulizer solution (2 milligrams/mL) ||See albuterol dose. ||Has not been studied in severe asthma exacerbations. Do not mix with other drugs. |
|MDI (370 micrograms/puff) ||See albuterol MDI dose. ||Has not been studied in severe asthma exacerbations. |
|Levalbuterol (R-albuterol) || || |
|Nebulizer solution (0.63 milligram/3 mL, 1.25 milligrams/3 mL) ||1.25–2.5 milligrams every 20 min for three doses, then 1.25–5 milligrams every 1–4 h, as needed. ||Levalbuterol administered in one half the milligram dose of albuterol provides comparable efficacy and safety. Has not been evaluated by continuous nebulization. |
|MDI (45 micrograms/puff) ||See albuterol MDI dose. || |
|Pirbuterol || || |
|MDI (200 micrograms/puff) ||See albuterol MDI dose. ||Has not been studied in severe asthma exacerbations. |
|Systemic (Injected) β2-Agonists |
|Epinephrine || || |
|1:1000 (1 milligram/mL) ||0.3–0.5 milligram every 20 min for three doses SC. ||No proven advantage of systemic therapy over aerosol. |
|Terbutaline || || |
|(1 milligram/mL) ||0.25 milligram every 20 min for three doses SC. ||No proven advantage of systemic therapy over aerosol. |
|Ipratropium bromide || || |
|Nebulizer solution (0.25 milligram/mL) ||0.5 milligram every 20 min for three doses, then as needed. ||May mix in same nebulizer with albuterol. Should not be used as first-line therapy; should be added to SABA therapy for severe exacerbations. The addition of ipratropium has not been shown to provide further benefit once the patient is hospitalized. |
|MDI (18 micrograms/puff) ||Eight puffs every 20 min, as needed, up to 3 h. ||Should use with valved holding chamber and face mask for children <4 y. Studies have examined ipratropium bromide MDI for up to 3 h. |
|Ipratropium with albuterol || || |
|Nebulizer solution (each 3-mL vial contains 0.5 milligram of ipratropium bromide and 2.5 milligrams of albuterol.) ||3 mL every 20 min for three doses, then as needed. ||May be used for up to 3 h in the initial management of severe exacerbations. The addition of ipratropium has not been shown to provide further benefit once the patient is hospitalized. |
|MDI (each puff contains 18 micrograms of ipratropium bromide and 90 micrograms of albuterol.) ||Eight puffs every 20 min as needed up to 3 h. ||Should use with valved holding chamber and face mask for children <4 y. |
|Systemic Corticosteroids || ||Applies to all three corticosteroids for oral medications. |
|Prednisone ||For inpatients: oral "burst," use 40–80 milligrams/d in one or two divided doses until PEFR reaches 70% of predicted or personal best. ||For outpatients: oral "burst," use 40–60 milligrams in single or two divided doses for 5–10 d. |
|Methylprednisolone ||IV: 1 milligram/kg every 4–6 h. ||For outpatients: a single IM dose of 150 milligrams depot methylprednisolone may be used.19 |
|Prednisolone ||1–2 milligrams/kg/d for 5–10 d; may be divided twice daily. ||More frequently used over prednisone in children due to increased palatably of available liquid formulations. |
β-Adrenergic drugs cause bronchodilation by stimulation of the enzyme adenyl cyclase, which converts intracellular adenosine triphosphate into cyclic adenosine monophosphate. This action enhances the binding of intracellular calcium to cell membranes, reducing the myoplasmic calcium concentration, and results in relaxation of bronchial smooth muscle. β-Adrenergic drugs also inhibit mediator release and promote mucociliary clearance.
The most common side effect of β-adrenergic drugs is skeletal muscle tremor. Patients also may experience nervousness, anxiety, insomnia, headache, hyperglycemia, palpitations, tachycardia, and hypertension. Clinical toxicity is rare and less common than undertreatment complications. Provoking dysrhythmias or myocardial ischemia is rare, especially in those without a prior history of coronary artery disease. The older catecholamine bronchodilators, such as epinephrine, are not β2 specific and have a short duration of action.
Albuterol is a 50:50 racemic mixture (equal amounts of left and right isomers); it is now available in the hydrofluoroalkane formulation, which has increased the cost and the effectiveness. The R isomer has great binding affinity for the β2-receptor and is responsible for bronchodilation. The S isomer has no bronchodilatory effect but has a long half-life (12 hours); this isomer may be responsible for late paradoxical bronchospasm in some patients. Levalbuterol (Xopenex®) is the pure R isomer form of the drug, intended to improve effectiveness and limit side effects such as tachycardia and rhythm change. Both racemic albuterol and levalbuterol can be given as intermittent or continuous nebulizations. Levalbuterol costs 5 to 25 times more than albuterol, and it has no clear advantage over albuterol regarding symptom change, admission, or tachycardia.15,16,17
Nonprescription racemic epinephrine (Asthmanefrin®) replaced Primatene® as an over-the-counter medication, and the cost is less than for prescription β2-adrenergics. Asthmanefrin® contains 11.25 milligrams of racemic epinephrine/0.5 mL. In one study, subjects recruited through local pharmacies reported no worse asthma outcomes than individuals treated with prescription β-agonists.18 No other data exist to guide use of Asthmanefrin® versus prescribed agents.
Aerosol therapy with β2-adrenergic drugs produces excellent bronchodilation and is favored over oral or parenteral routes. The aerosol route achieves topical administration of a relatively small dose of drug, thereby producing local effects with minimum systemic absorption and fewer side effects. Aerosol delivery occurs with a metered-dose inhaler coupled to a spacing device or with a compressor-driven nebulizer.20 A spacing device attached to the inhaler improves drug deposition; when optimally used, metered-dose inhaler therapy delivers the most drug to target airways, better than nebulized therapy. Even with optimum technique, a maximum of 15% of the drug dose is retained in the lungs, regardless of the aerosol method used.
Aerosol treatments may be administered every 15 to 20 minutes or on a continuous basis.21 Subcutaneous epinephrine and terbutaline are options for patients unable to coordinate aerosolized or metered-dose inhaler treatments, seen often in severe airflow-limited states. IV β-agonist infusions offer no advantage over aerosolized or metered-dose inhaler–delivered agents and carry increased risk.22
Salmeterol xinafoate and formoterol are β2-adrenoreceptor agonists that bind with greater affinity to the β2-receptor site than albuterol. They are indicated for twice-daily maintenance therapy. Neither drug should be used for acute asthma exacerbations. Bronchodilator effects last at least 12 hours, and tachyphylaxis has not been reported with long-term use. The number of asthma-related deaths among patients receiving salmeterol, especially in African Americans, has increased for unknown reasons, although this may be due to failure to recognize the need for or use rescue short-acting agents and to seek care appropriately. Long-acting β2-adrenoreceptor agonists are an effective treatment for long-term control of asthma, especially in conjunction with inhaled corticosteroids. Short-acting β2-adrenoreceptor agonists are used for infrequent or breakthrough symptoms that occur despite the use of long-acting β2-adrenoreceptor agonists.7,8,9,10,21
Corticosteroids are a cornerstone of asthma treatment. Steroids produce beneficial effects by restoring β-adrenergic responsiveness and reducing inflammation. The peak anti-inflammatory effect occurs at least 4 to 8 hours after IV or PO administration, but early use is wise to enhance care quickly; corticosteroids given within 1 hour of arrival in the ED reduce the need for hospitalization.23 Although there is disagreement over the optimal dose in acute asthma, an initial dose of PO prednisone of 40 to 60 milligrams or IV methylprednisolone of 1 milligram/kg is sufficient, and higher-dose corticosteroid therapy offers no advantage.24 Admitted patients should receive additional daily corticosteroids until subjective and objective improvements are achieved. Patients who are being discharged home with an FEV1 or PEF of <70% predicted after aggressive ED treatment should be prescribed a 5- to 10-day nontapering course of prednisone (40 to 60 milligrams/d in a single daily dose or its equivalent) or a 2-day course of oral dexamethasone (16 milligrams/d in a single daily dose).7,8,9,10,19,25,26 A single dose of depot methylprednisolone, 150 milligrams IM, is another option if compliance is a concern.27
Current recommendations favor inhaled corticosteroids for all patients with mild persistent asthma or more severe asthma.7,8,9,10 This means discharging patients with mild persistent or more severe asthma on maintenance inhaled corticosteroids in addition to any systemic bursts.28,29,30,31 Inhaled corticosteroid options are beclomethasone, 80 to 240 micrograms/d; budesonide, 180 to 600 micrograms/d; flunisolide, 500 to 1000 micrograms/d; fluticasone, 88 to 264 micrograms/d; mometasone, 200 micrograms/d; and triamcinolone acetonide, 300 to 750 micrograms/d.
The effects of anticholinergics used in combination with β-adrenergic agents are additive. Anticholinergics affect large, central airways, whereas β-adrenergic drugs dilate smaller airways. Anticholinergic drugs competitively antagonize acetylcholine at the postganglionic junction between the parasympathetic nerve terminal and effector cell. This process blocks the bronchoconstriction induced by vagal cholinergic-mediated innervation to the larger central airways. In addition, anticholinergics reduce concentrations of cyclic guanosine monophosphate in airway smooth muscle, further promoting bronchodilation.
The anticholinergic commonly used is inhaled ipratropium bromide. Ipratropium is available as a nebulized solution and a metered-dose inhaler or in combination with albuterol7,8,9,10 (Table 69-5). Use an aerosolized ipratropium bromide solution, 0.5 milligrams, in patients with moderate to severe exacerbation.7,8,9,10 Adding multiple doses of ipratropium bromide to a short-acting selective β-agonist may improve bronchodilation and decrease the need for hospitalization among severely obstructed asthmatics,32 although this benefit is not universal.33 Potential side effects with anticholinergics include dry mouth, thirst, and difficulty swallowing. Less commonly, tachycardia, restlessness, irritability, confusion, difficulty in micturition, ileus, blurring of vision, or an increase in intraocular pressure can occur. Long-acting anticholinergic agents have no role in acute care.