Asthma remains a significant cause of morbidity and mortality throughout the world. Patients presenting with near-fatal asthma provide a unique population in which to study the variables that contribute to asthma-related mortality. By identifying high-risk patients, using objective and subjective measures to detect severe exacerbations, and initiating early medical intervention, the morbidity and mortality of asthma can be reduced.
In the May 2005 issue of The Journal of Respiratory Diseases, we reviewed the risk factors associated with life-threatening asthma. In this article, we will focus on management strategies.
Standard therapies for severe asthma include ß-agonists, oxygen, and corticosteroids (Table). ß-Agonists remain first-line therapy for patients with exacerbations of any degree of severity (Figure 1).1 These agents, with the exception of the long-acting agents, induce bronchodilation with a rapid onset of action. Patients with life-threatening asthma may have significant bronchoconstriction, airway edema, and inflammation, and may require high doses or repeated doses of ß-agonists before showing a sufficient response.
Numerous studies have indicated that administration of ß-agonists via metered-dose inhaler with spacer is as effective as nebulized treatments.2,3 Reports in the litera-ture suggest that continuous nebulization may be beneficial in the most severe asthma exacerbations.4 Levalbuterol, an isomer of racemic albuterol, may play a role in managing refractory asthma,5 particularly in patients with ischemic heart disease or severe tachycardia. Levalbuterol is reported to have fewer side effects, since the bronchodilatory effects of albuterol result from activity of the R-isomer, while the side effects may result from the S-isomer.5 In a subset of patients with severe asthma, a dose-dependent relationship existed when higher doses of levalbuterol were used.6
Nebulized doses of levalbuterol range from 0.63 to 1.25 mg in adults, but a dose of 2.5 mg should be considered in those with severe asthma. One study demonstrated a dose-response curve with doses ranging from 0.31 to 2.5 mg in children with severe exacerbations.6
Intravenous ß-agonists have not been shown to be of more benefit than inhaled ß-agonists in European studies.7,8 Although most patients respond to inhaled ß-agonists, some may benefit from systemic treatment. Appel and associates9 performed a randomized controlled trial of patients with acute asthma. In this double-blind cross-over study, patients with a peak expiratory flow rate (PEFR) of less than 150 L/min received inhaled metaproterenol or subcutaneous epinephrine(Drug information on epinephrine). At 120 minutes, 61% of those who received metaproterenol had improved PEFR, compared with 89% of those who received epinephrine. Patients in whom initial therapy failed had symptoms for a significantly longer duration before presentation, suggesting that marked inflammation and mucous plugging may result in a suboptimal response to inhaled medications.9 The results of this study do not clearly define the role of systemic ß-agonists in the treatment of life-threatening asthma, but they suggest that a trial of subcutaneous ß-agonists should be considered in patients who fail to respond to inhaled medications.
Epinephrine can be administered subcutaneously as 0.3 to 0.5 mg of a 1:1000 solution every 20 minutes to a maximum of 3 doses. Terbutaline(Drug information on terbutaline), 0.25 to 0.5 mg, should be used in pregnant patients requiring subcutaneous ß-agonist treatment. Although there is some concern about using systemic ß-agonists in older patients, Cydulka and associates10 showed that patients older than 40 years had minimal risk of side effects from subcutaneous epinephrine if they had no active angina and no history of myocardial infarction in the previous 6 months.Systemic corticosteroids
Corticosteroids should be administered to all patients presenting to the hospital with asthma unless PEFR or forced expiratory volume in 1 second (FEV1) is at least 80% of predicted after 1 hour of treatment (Figure 2). Systemic corticosteroids decrease inflammation, increase the number and sensitivity of ß-receptors, and inhibit the migration and function of eosinophils and neutrophils.11
A meta-analysis of 700 articles with 30 randomized, controlled trials demonstrated that corticosteroid administration in the emergency department (ED) reduced admission rates and decreased relapse rates at 7 to 10 days.12 Oral therapy was equivalent to intravenous therapy. Corticosteroids were most effective in patients with severe asthma who were not receiving longterm corticosteroid therapy.
Because the maximum effect of corticosteroids is not seen until 4 to 6 hours after administration, this therapy should be instituted early (within 1 hour of presentation). The optimal dose remains controversial. Haskell and associates13 randomized patients with severe asthma to receive 125, 40, or 15 mg of methylprednisolone(Drug information on methylprednisolone) every 6 hours. Medium and high doses caused more significant improvement than did low doses. The highdose group had a more rapid improvement in the first 24 to 36 hours of therapy.
We prefer using 125 mg of methylprednisolone every 6 hours for the first 24 to 48 hours in patients admitted to the ICU. The practice guidelines published by the NIH recommend prednisone(Drug information on prednisone), 120 to 180 mg/d in 3 or 4 divided doses (or the equivalent) for 48 hours, then 60 to 80 mg/d until PEFR reaches 70% of predicted or personal best.13 The guidelines also state that no advantage has been identified for higher doses or intravenous administration if GI absorption is normal.14
If patients have improvement on this regimen, they may be switched to oral prednisone, 60 to 80 mg (1 mg/kg) per day. Treatment should be continued for 3 to 10 days, then discontinued without a taper if the patient is receiving inhaled corticosteroid therapy. Inhaled corticosteroids should be continued during systemic treatment to avoid rebound bronchoconstriction with discontinuation of systemic therapy.Anticholinergics
Ipratropium has been shown to be beneficial in managing acute bronchospasm induced by ß-blockers and monoamine oxidase inhibitors. 15 Patients with severe airway obstruction (FEV1 of less than 50% of predicted) also benefit from ipratropium in combination with ßagonists. In such patients, the combined use of anticholinergics and ß-agonists improves PEFR and FEV1 more than ß-agonists alone and significantly decreases the risk of hospital admission.16
The onset of action of anticholinergics in patients with acute exacerbations of asthma is short, occurring within 1 minute, with peak effects within 20 minutes.15 Benefits may persist for up to 48 hours.16 Anticholinergic therapy should be continued until the patient stabilizes but should not be added to the patient’s long-term asthma management regimen.