Salmeterol does not compromise the bronchodilator response to albuterol during acute episodes of asthma

doi:10.1016/S0002-9343(99)00222-3

The American Journal of Medicine

Volume 107, Issue 3, September 1999, Pages 209-213

https://doi.org/10.1016/S0002-9343(99)00222-3 Get rights and content

Abstract

PURPOSE: The present study was undertaken to determine whether regular use of salmeterol reduces the emergency effectiveness of albuterol.

PATIENTS AND METHODS: Acutely ill asthmatic patients chronically taking salmeterol, and similar patients who were not taking salmeterol, were treated with albuterol, either as three aerosols of 2.5 mg every 20 minutes for 1 hour or two doses of 5.0 mg every 20 minutes. Peak expiratory flow measurements were monitored before and after each treatment. The time to disposition and the number of return visits were also recorded.

RESULTS: One hundred fourteen patients, 57 who took salmeterol and 57 who served as control patients, completed the study. Thirty-three patients in each group received the lower dose of albuterol, and 24 were given the larger amount. There were no significant pretreatment differences between the salmeterol and control groups in the severity of symptoms or the degree of airway obstruction. Both albuterol regimens improved peak flow. Responses in the control group and in the salmeterol group were similar (low-dose albuterol increase in peak flow = 49%, control = 35%, P = 0.37; high-dose albuterol increment in peak flow = 43%, control = 41%, P = 0.81). 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.

CONCLUSIONS: In patients with asthma, chronic use of salmeterol doses not interfere with the effects of standard doses of albuterol for the treatment of acute decompensations.

Section snippets

Material and methods

Asthmatic patients, 17 years of age or older, who came to the emergency department of University Hospitals in Cleveland, Ohio, with an acute exacerbation of their illness were eligible for participation. Those who indicated that they were using salmeterol for chronic control of asthma were selected for study. Each patient taking salmeterol was matched with a patient who was not using salmeterol who had presented to the emergency department within a few days (mean, 1.5 days). No other selection

Results

We enrolled 114 acutely ill patients with asthma, including 57 who took salmeterol and 57 control patients. Thirty-three patients in each group received the low dose of albuterol (three treatments with 2.5 mg), and 24 were given the larger dose (two treatments with 5 mg). On average, the patients had moderately severe episodes of bronchospasm and were well matched as to age, sex, signs, symptoms, and the severity of obstruction (Table). More patients in the salmeterol group were using their

Discussion

Our results demonstrate that the chronic use of salmeterol does not interfere with the management of acutely ill asthmatic patients in an emergency setting. Patients taking salmeterol readily respond to treatment with albuterol, its active moiety: there were no differences in the magnitude of bronchodilation, the rate of resolution of the attacks, the proportion of admissions, or the time spent in the emergency department between them and control patients who were not taking salmeterol.

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Safety and Effectiveness of As-Needed Formoterol in Asthma Patients Taking Inhaled Corticosteroid (ICS)-Formoterol or ICS-Salmeterol Maintenance Therapy
2023, Journal of Allergy and Clinical Immunology: In Practice
As-needed low-dose inhaled corticosteroid (ICS)-formoterol reliever is recommended in patients with asthma prescribed maintenance ICS-formoterol. Clinicians often ask whether ICS-formoterol reliever can be used with other maintenance ICS-long-acting β₂-agonists.
To evaluate the safety and effectiveness of as-needed formoterol in patients taking maintenance ICS-formoterol or ICS-salmeterol from the RELIEF study.
RELIEF (SD-037-0699) was a 6-month, open-label study that randomized 18,124 patients with asthma to as-needed formoterol 4.5 μg or salbutamol 200 μg on top of maintenance therapy. This post hoc analysis included patients on maintenance ICS-formoterol or ICS-salmeterol (n = 5436). The primary safety outcome was a composite of serious adverse events (SAEs) and/or adverse events leading to discontinuation (DAEs); the primary effectiveness outcome was time-to-first exacerbation.
For both maintenance groups and both relievers, similar numbers of patients had ≥1 SAE and/or DAE. In patients taking maintenance ICS-salmeterol, but not ICS-formoterol, significantly more non-asthma-related and nonserious DAEs occurred with as-needed formoterol versus as-needed salbutamol (P = .0066 and P = .0034, respectively). In patients taking maintenance ICS-formoterol, there was a significantly lower risk in time-to-first exacerbation with as-needed formoterol versus as-needed salbutamol (hazard ratio [HR]: 0.82, 95% confidence interval [CI]: 0.70, 0.95; P = .007). In patients taking ICS-salmeterol maintenance, time-to-first exacerbation was not significantly different between treatment arms (HR: 0.95, 95% CI: 0.84, 1.06; P = .35).
As-needed formoterol significantly reduced exacerbation risk compared with as-needed salbutamol when added to maintenance ICS-formoterol, but not to maintenance ICS-salmeterol. More DAEs were seen with ICS-salmeterol maintenance therapy plus as-needed formoterol. Further research is needed to assess whether this is relevant to as-needed combination ICS-formoterol.
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The use of long acting β<inf>2</inf>-agonists, alone or in combination with inhaled corticosteroids, in Chronic Obstructive Pulmonary Disease (COPD): A risk-benefit analysis
2011, Pharmacology and Therapeutics
Citation Excerpt :
The outcome of this may have been relatively low receptor occupancy even in the salmeterol group. Korosec et al. (1999) recruited asthmatic patients entering the emergency department of University Hospitals in Cleveland, Ohio with an acute exacerbation of asthma. Those who indicated they were using salmeterol for chronic control of asthma were selected for study and matched with a patient not taking salmeterol who had presented to the emergency department within a few days.
Chronic Obstructive Pulmonary Disease (COPD) is a slowly progressive, largely non-reversible pulmonary disease which is characterised by airflow limitation. It is one of the few diseases with an increasing mortality rate and by 2020 it is predicted to be the third leading cause of death. The mainstays of current treatment are long acting β₂ agonists (LABAs) coupled with an increasing reliance on inhaled corticosteroids (ICS). Two LABAs (salmeterol and formoterol) are currently licenced for COPD both as monotherapy and in combination with ICS (fluticasone propionate (FP) and budesonide respectively). A comprehensive review of the risk–benefit of these medicines in COPD is provided here which concludes that there is limited efficacy for LABAs in COPD either alone or in combination with ICS and no overall modification of the disease process. However, where directly compared, combination therapy usually provides an advantage over monotherapy. Importantly the apparent effectiveness of treatment may significantly depend upon the outcome measure chosen with some measures possibly underestimating the extent of benefit. ICS benefit may also be greater in those patients who respond to treatment. Set against this benefit are recent concerns that a number of issues related to the clinical trial design such as prior use of ICS and different withdrawal rates between groups may be significantly influencing results. Furthermore there is no evidence of a dose response relationship with regard to ICS dose. A key issue with combination therapy is the excess risk of pneumonia conferred by the use of an ICS in this patient population. This risk does not appear to be proportional to the ICS dose but may differ between FP and budesonide. We conclude that further studies are required to identify the optimal dose of ICS, in terms of both risk and benefit, and to confirm their benefit in steroid naïve patients. Furthermore it will be important to determine whether the risk of pneumonia is apparent with both FP and budesonide and to identify factors which may predict steroid responsiveness in COPD.
Salmeterol use and risk of hospitalization among emergency department patients with acute asthma
2010, Annals of Allergy, Asthma and Immunology
Citation Excerpt :
Conversely, even after adjusting for confounders, the salmeterol monotherapy patients (group B) still showed a higher risk of hospitalization. To our knowledge, only 1 prior study has examined this issue but was limited by small sample size (n = 114) at a single site, lacked adjustment for potential confounders, and lacked patients undergoing ICS therapy.26 Thus, our study adds novel data to the ongoing debate from the ED setting.
The safety of inhaled long-acting β₂-agonists (LABAs) in the treatment of chronic asthma remains controversial and has not been evaluated in emergency department (ED) patients with acute asthma.
To determine whether ED patients undergoing long-term LABA therapy would have increased risk of asthma-related hospitalization compared with those not undergoing LABA therapy and whether concurrent long-term inhaled corticosteroid (ICS) therapy would mitigate this risk.
Prospective cohort study of patients aged 12 to 54 years with acute asthma in 115 EDs. Four patient groups were created based on their asthma regimen: no ICS or salmeterol (group A), salmeterol monotherapy (group B), ICS monotherapy (group C), and combination ICS and salmeterol (group D).
Of the 2,236 included patients, group A had 1,221 patients (55%), group B had 48 patients (2%), group C had 787 patients (35%), and group D had 180 patients (8%); 489 patients (22%) required hospitalization. In a multivariable model controlling for 20 factors and using group A as the reference, group B had an increased risk of hospitalization (odds ratio [OR], 2.2; 95% confidence interval [CI], 1.0–4.9), whereas groups C (OR, 1.1; 95% CI, 0.8–1.5) and D (OR, 1.2; 95% CI, 0.8–1.9) did not.
Among ED patients with acute asthma, those undergoing salmeterol monotherapy had an increased risk of hospitalization; however, this risk was not seen among patients undergoing combination ICS-salmeterol therapy. Our findings provide data from a unique ED population on clinical response to acute asthma treatment among patients undergoing long-term LABA therapy.
Rationale for the major changes in the pharmacotherapy section of the National Asthma Education and Prevention Program guidelines
2007, Journal of Allergy and Clinical Immunology
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Tolerance induced from LABAs reduces the response to short-acting β2-agonists after moderate bronchospasm induced by methacholine, but it only takes one additional dose to produce the same degree of bronchodilation.45-47 In addition, a trial in patients presenting to the emergency department demonstrated no difference in bronchodilator response to short-acting β2-agonists in patients previously receiving LABAs and those not receiving LABAs.48 Neither short- nor long-term administration of LABAs induces an increase in bronchial responsiveness similar to that seen with administration of short-acting β2-agonists.40-42
Numerous changes have been incorporated into the new National Asthma Education and Prevention Program's Expert Panel Report 3. In the pharmacotherapy section of the report, many of these changes are minor in that they do not alter the basic philosophy of treatment recommendations from the previous Expert Panel Report but only add new formulations, change dosing or dosage forms, or add discussion of risks. However, 4 major changes have been identified, and the rationales for 3 are discussed in detail here. The treatment of childhood asthma is divided into 2 distinct age groups, infants less than 5 years of age and children 5 to 12 years of age, because of the availability of more data suggesting differences in response in these patients, as well as a relative paucity of quality data in the younger patients. Omalizumab, a humanized mAb to IgE, is the only new entity approved for the treatment of asthma since the previous guidelines, and its recommendations were reviewed. The indication for combination therapy with inhaled corticosteroids and long-acting inhaled β₂-agonists (LABAs) has been modified in lieu of the recent black box warning concerning the increased risk of severe asthma exacerbations and death associated with LABA use. However, the inhaled corticosteroids/LABAs are still recommended for patients with moderate-to-severe persistent asthma. The rationale for the continued recommendation is provided.
Formoterol induces tolerance to the bronchodilating effect of Salbutamol following methacholine-provocation test in asthmatic children
2006, Pulmonary Pharmacology and Therapeutics
To study whether Formoterol treatment affect the bronchodilator response to salbutamol after methacholine-provocation test (MPT) in asthmatic children.
A prospective, double-blind, randomized, placebo-controlled study. Children aged 7–16 years with mild-persistent to moderate asthma treated with inhaled corticosteroids, were enrolled. After 2-weeks of run-in period, subjects were randomized to inhaled Formoterol 9 μg bid (n=19) or placebo (n=19) for 2 weeks. MPT with salbutamol-recovery curve was performed at the beginning and at the end of the trial period. Measurements of peak expiratory flow rate (PEFR), symptoms score, rescue bronchodilator usage and side effects were recorded daily. The primary end-points were the change in FEV₁ 0–10 min after salbutamol inhalation and the recovery time from 80 to 100% of pretest FEV₁. Statistical analyses were performed by ANOVA with repeated measures.
There was a decrease in the bronchodilator response to salbutamol and an improved PEFR in the Formoterol group. There was no difference in all other parameters.
Formoterol decreases the bronchodilator response to salbutamol following MPT. Whether this phenomenon has clinical implication during acute asthma needs further studies.

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^☆: Supported in part by Specialized Center of Research (SCOR) Grant HL-37117 from the National Heart, Lung, and Blood Institute and General Clinical Research Center Grant MO-1-RR00080 from the National Center for Research Resources, National Institutes of Health, United States Public Health Service.

^∗: Access the “Journal Club” discussion of this paper at http://www.elsevier.com/locate/ajmselect/

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Clinical StudiesSalmeterol does not compromise the bronchodilator response to albuterol during acute episodes of asthma∗☆,

Abstract

Section snippets

Material and methods

Results

Discussion

Lancet

Am J Med

Am J Med

Chest

Am J Med

Observations on the effects of aerosolized albuterol in acute asthma

Am J Respir Crit Care Med

Expiratory peak flow rate. Standard values for normal subjects. Use as a clinical test of ventilatory function

Am Rev Respir Dis

Clinical Studies
Salmeterol does not compromise the bronchodilator response to albuterol during acute episodes of asthma∗☆,