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Dr. Donohue has research contracts and is on the Speakers’ Bureau for Glaxo Wellcome, the manufacturer of salmeterol. Dr. Donohue is Professor of Medicine, Division of Pulmonary and Critical Care Medicine, University of North Carolina School of Medicine, Chapel Hill, NC.
Correspondence to: James F. Donohue, MD, FCCP, Department of Medicine, CB#7020, 420 Burnett-Womack Building, Chapel Hill, NC 27599-7020; e-mail: jdonohue{at}med.unc.edu
The long-acting ß2-agonist salmeterol has been approved for chronic maintenance therapy in asthma1 and COPD.2 Previous studies were conducted on outpatients who were well controlled with no comorbidity factors. Because of its relative slow onset of action, salmeterol is not indicated for relief of acute bronchospasm. However, exposure to this agent is unavoidable in the acute setting where, in fact, salmeterol may have unique benefits and risks. Clinicians need more information on the use of this agent in relevant settings such as the emergency department, ICU, medical and pediatric wards, operating room, and labor and delivery suites. Hospitalized patients are often acutely ill, and may be receiving large doses of concurrent medications such as short-acting ß-agonists, theophylline, corticosteroids, anesthetics, and analgesics. Furthermore, patients may be under physiologic stresses, such as pregnancy or surgery. Data on the safety of salmeterol in the hospital setting are slowly being compiled; information on benefits such as decreased length of stay, decreased costs, and improved clinical outcomes are not yet available. A number of issues concerning the use of salmeterol in the hospital are raised:
1. Are patients who receive this agent at greater risk of having acute asthma or increased mortality?
Lanes et al,3 in the study of > 61,000 US asthmatic patients, of whom 2,708 were using salmeterol, demonstrated that after adjusting for severity, salmeterol users were at no greater risk of asthma-related hospitalization, emergency department visits, or ICU stay. A case-controlled study4 from the United Kingdom found that users of salmeterol were at no greater risk of a near-fatal asthma attack. In fact, salmeterol reduced the frequency of severe exacerbations and requirement for emergency medical assessment.5 There was no increased risk of either nonfatal cardiac failure or nonfatal ischemic heart disease among salmeterol users,6 nor was there any increase in asthma mortality with up to 16 weeks of medication use. A recent review by Beasley and colleagues7 examined the issue of the use of ß-agonists and the risk of asthma morbidity and mortality. While fenoterol and isoproterenol may be associated with worsening of asthma control, particularly in the setting of hypoxemia, sufficient studies were not available to address the risk associated with salmeterol. In general, salmeterol is not associated with significant worsening of asthma control or increased frequency of severe attacks. If a near-fatal attack is considered to be an intermediate step in a process by which a severe attack may become fatal, salmeterol is unlikely to be associated with significantly increased risk of death.7
2. Is the treatment of an acute asthma attack compromised by maintenance therapy with salmeterol?
Korosec et al8 found that salmeterol use does not compromise the bronchodilator response to albuterol during acute episodes of asthma. An emergency department study of 114 patients, 57 who took salmeterol and 57 who did not, revealed similar responses to albuterol. There were no significant differences between the control group and the salmeterol group in the mean length of stay, the proportion of subjects admitted to the hospital, or the number of return visits to the emergency department.
3. Can salmeterol be safely used in hospitalized patients, and does it provide additional benefit?
Here, the study by Peters et al in this issue of CHEST (see page 313) provides preliminary guidance. No adverse effects were noted with the regular use of salmeterol in the ward setting. As for efficacy, patients receiving salmeterol as an adjunct to conventional therapy had greater FEV1 levels than the placebo group at 12, 24, 36, and 48 h, although they were not statistically significant. At 48 h compared to baseline, there was significant improvement in the FEV1 and FVC, especially for those with initial levels of FEV1 of < 1.5 L. This study was directed by academic physicians and cannot yet be extrapolated to a real-world setting. Misuse of metered-dose inhalers by hospitalized patients is widespread.9 Other important questions to be addressed concern the role of salmeterol in the ICU, including its use on-line in a ventilator circuit. The second objective of Peters et al, to improve patient outcomes by reducing the required dose of albuterol and to shorten the length of hospitalization, remains to be accomplished.
4. What are the risks of salmeterol taken concurrently with albuterol?
In outpatient trials of patients receiving salmeterol, the cardiovascular response to albuterol by metered-dose inhaler and nebulizer using 24 h continuous Holter monitor revealed occasional supraventricular ectopic beat, but little change overall in the heart rate and QTc interval.10 In a study by Smyth et al,11 patients received up to 200 µg of salmeterol followed by inhaled albuterol, with cumulative doses of up to 3,600 µg producing a change in heart rate of 14.4 beats/min and a change in serum potassium of - 0.048 µmol/L. Physicians must take into account these additive effects. Theophylline has also been safely given to outpatients receiving salmeterol; inpatient data are not available.
5. What about the use of salmeterol in patients with significant comorbidities?
While continuous ECG Holter monitoring data from two large COPD clinical trials are reassuring, these patients were not acutely ill or hospitalized, nor did they have underlying cardiac disease. Very little data are available concerning patients receiving salmeterol with underlying disease. A small study12 concluded that adverse cardiac events could occur in COPD patients with preexisting cardiac arrhythmias and hypoxemia if they use long-acting ß-agonists, although single doses of salmeterol, 50 µg, and formoterol, 12 µg, had a relatively better safety margin than formoterol, 24 µg.
Since salmeterol is often a component of outpatient therapy with inhaled corticosteroids, it may be logical to start therapy prior to discharge. Earlier use, as an adjunct to conventional therapy initiated within 8 to 12 h of admission to the medical wards, appears to be safe and may be beneficial. More observations on hospitalized patients are needed.
References
This article has been cited by other articles:
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  P Phipps and C S Garrard The pulmonary physician in critical care * 12: Acute severe asthma in the intensive care unit Thorax, January 1, 2003; 58(1): 81 - 88. [Abstract] [Full Text] [PDF]
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 P.J. Barnes Scientific rationale for inhaled combination therapy with long-acting {beta}2-agonists and corticosteroids Eur. Respir. J., January 1, 2002; 19(1): 182 - 191. [Abstract] [Full Text] [PDF]
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