Effects of Ipratropium Bromide Nebulizer Solution with and without Preservatives in the Treatment of Acute and Stable Asthma

doi:10.1378/chest.102.3.742

Chest

Volume 102, Issue 3, September 1992, Pages 742-747

https://doi.org/10.1378/chest.102.3.742 Get rights and content

In a recent study, it was suggested that the preservatives in ipratropium bromide nebulizer solution may cause a paradoxic bronchoconstrictor response in 20 percent or more of patients with stable asthma. The frequency of this response in patients with acute asthma is unknown. The aim of this study was to examine the acute effects of the usual dose of nebulized ipratropium bromide (0.25 mg) in patients with either stable or acute asthma using formulations with and without added preservatives. Twenty-five patients with stable asthma and 25 patients with acute asthma were studied. Each subject was given preservative-containing ipratropium bromide, preservative-free ipratropium bromide, pH 7 preservative-free ipratropium bromide, and saline solution in random order using a double-blind crossover technique with at least 4 h between drug administrations. Very frequent measurements of FEV₁ were made for 30 min after each drug administration and then 5 mg of albuterol was nebulized and the FEV₁ was measured again after another 30 min. Changes in FEV₁ were expressed as a percentage of the predicted FEV₁. Paradoxic bronchoconstriction to ipratropium was detected in only one patient with acute asthma (12 percent fall in FEV₁) but in none of the patients with stable asthma. A 6 percent fall in FEV₁ change occurred with the saline solution in this subject suggesting that the response may have been a nonspecific one due to increased bronchial responsiveness. The mean response (± 1 SD) to albuterol plus either preservative-containing ipratropium, preservative-free ipratropium, or pH7 preservative-free ipratropium was significantly greater (p<0.05) than the response to albuterol alone both in the patients with acute asthma (25 ± 12 percent, 27 ± 15 percent, 26 ± 15 percent, and 20 ± 15 percent, respectively) and stable asthma (26 ± 7 percent, 25 ± 8 percent, 24 ± 6 percent, and 22 ± 9 percent) supporting the use of ipratropium bromide as an additional bronchodilator in patients with asthma who do not show a satisfactory response to nebulized β-adrenergic agonist.

Section snippets

Patients

Twenty-five patients with stable asthma and 25 patients with acute asthma took part in the study and their characteristics are described in Table 1. No attempt was made to select patients, and subjects presenting consecutively were approached for inclusion in the study. All patients had documented reversible airways obstruction within one month of inclusion of the study (FEV₁ increased by 20 percent or more 15 min after the inhalation of 200 µg of albuterol from a metered dose inhaler) and

Results

All patients completed the study. There was no significant difference (p>0.05) between the mean (± 1 SD) baseline FEV₁ value prior to each of the tests of the patients with stable (1.79 ± 0.52 L, 1.80 ± 0.55 L, 1.81 ± 0.52 L, 1.78 ± 0.53 L) or acute asthma (1.24 ± 0.47 L, 1.26 ± 0.46 L, 1.25 ± 0.44 L, 1.22 ± 0.43 L). Similarly, there was no significant difference among the age, sex, and atopic status of the two groups of patients although those with acute asthma did have a greater

Discussion

In this study, the inhalation of 1 ml (0.25 mg) ipratropium bromide nebulizer solution, the most widely used dose for the treatment of moderate bronchospasm in the community, did not cause paradoxic bronchoconstriction in any of the subjects with stable asthma and in only one of the subjects with acute asthma. These results contrast with those reported previously of patients with stable asthma in whom it was found that 4 ml of preservative-containing ipratropium produced a fall in FEV₁ of 20

ACKNOWLEDGMENTS

The authors would like to thank the respiratory physicians from St. Vincent's Hospital who agreed to allow their patients to be included in this study. We would also like to thank Boehringer Ingelheim Pty Ltd for the preparation and donation of the ipratropium solutions that were used in this study.

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Cited by (27)

Acute severe asthma
2013, Oh's Intensive Care Manual, Seventh Edition
Low incidence of paradoxical bronchoconstriction in asthma and COPD patients during chronic use of Respimat® soft mist™ inhaler
2005, Respiratory Medicine
Respimat^® Soft Mist™ Inhaler (SMI) is a new-generation inhaler that offers improved lung deposition compared with chlorofluorocarbon metered dose inhalers (CFC-MDIs). Bronchodilators administered via Respimat^® SMI are preserved and stabilised with low concentrations of benzalkonium chloride and ethylene diamine tetra-acetic acid, both of which have been reported to cause dose-related paradoxical bronchoconstriction. The aim of this analysis was to compare the incidence of paradoxical bronchoconstriction after chronic use of bronchodilators via Respimat^® SMI and CFC-MDI.
Data from three clinical trials, in which patients with asthma or chronic obstructive pulmonary disease (COPD) received ipratropium bromide alone or in combination with fenoterol hydrobromide, or placebo via Respimat^® SMI or CFC-MDI for 12 weeks, were included in the analysis. In order to evaluate the risk of paradoxical bronchoconstriction, we identified four respiratory events that might have occurred within 30 min of inhalation on four test days; these were: ‘bronchospasm’, ‘other respiratory adverse events’, ‘rescue medication use’ and ‘asymptomatic drop in FEV₁ ⩾15% from baseline’.
In total, 631 asthma and 1538 COPD patients participated in the three studies. No occurrences of bronchospasm were reported with Respimat^® SMI on any test day. Overall, the incidence of respiratory events possibly indicative of paradoxical bronchoconstriction was low and similar for both devices. There was no increase in the incidence of events during 12 weeks’ treatment.
Delivery of bronchodilators by Respimat^® SMI is safe with regard to paradoxical bronchoconstriction during chronic use in patients with asthma or COPD.
A randomized, placebo-controlled study to evaluate the role of salmeterol in the in-hospital management of asthma
2000, Chest
Citation Excerpt :
Also, bronchodilators may demonstrate different pharmacodynamic and pharmacokinetic characteristics during an acute exacerbation of asthma. Contrary to studies in stable asthma, Bryant and Rogers7 detected a significant response to ipratropium, another slow-onset, long-acting bronchodilator, within 1 min and a mean time to reach the peak effect of FEV1 within 17 min in patients with acute asthma. The optimal dose and dosing interval for salmeterol in patients with acute asthma are not known.
To assess the safety and efficacy of salmeterol xinafoate as an adjunct to conventional therapy for the in-hospital management of acute asthma.
A prospective, double-blind, randomized placebo-controlled trial.
Medical wards of a large university-based hospital.
Forty-three patients admitted for an acute exacerbation of asthma.
Salmeterol (42 μg) or two puffs of placebo every 12 h in addition to standard therapy (short-acting β-agonists, corticosteroids, and anticholinergic agents).
No clinically adverse effects were seen with the addition of salmeterol to conventional therapy. After salmeterol, there was no difference in pulse, respiratory rate, oxygen saturation by pulse oximetry, severity of symptoms, or dyspnea score. Patients receiving salmeterol had greater FEV₁ percent improvements than the placebo group at 12, 24, 36, and 48 h. These findings were not statistically significant. By paired Student's t tests, there were significant improvements in FEV₁ (p = 0.03) and FVC (p = 0.03) in the salmeterol group after 48 h of treatment with no comparable improvement in the placebo group. In a subgroup analysis of patients with an initial FEV₁ ≤ 1.5 L, the absolute FEV₁ percent improvement for salmeterol vs placebo was 51% vs 16% at 24 h and 54% vs 40% at 48 h. The relative FEV₁ percent improvement for salmeterol vs placebo was 17% vs 8% at 24 h and 18% vs 14% at 48 h.
The addition of salmeterol to conventional therapy is safe and may benefit hospitalized patients with asthma. Further studies are needed to clarify its role in the treatment of acute exacerbation of asthma.
A meta-analysis of the effects of ipratropium bromide in adults with acute asthma
1999, American Journal of Medicine
Purpose: To review the literature to determine whether inhaled ipratropium bromide provides additive benefits to adults with acute asthma who are being treated with beta-agonists in an emergency department.
SUBJECTS AND METHODS: English-language studies, both published (1978 to 1999) and unpublished, were retrieved using Medline, Science Citation Index, Current Contents, bibliographic reviews of primary research, review articles, consultation with experts, and the register of Medical Editors’ Trial Amnesty. Only randomized, double-blind, controlled trials that enrolled patients having an exacerbation of asthma were included. The main outcome measure was pulmonary function; hospital admission rate was also evaluated.
RESULTS: Ten studies including 1,483 adults with acute asthma were selected (mean age 32 ± 13 years, 36% men). The overall effect size in SD units of pulmonary function showed a significant benefit from ipratropium (effect size 0.14, 95% confidence interval [CI]: 0.04 to 0.24, P = 0.008). Study-specific effect sizes ranged from 0.03 to 0.63. This pooled effect size was equivalent to a 10% (95% CI: 2% to 18%) increase in forced expiratory volume in 1 second (FEV₁) or peak expiratory flow in the ipratropium group compared with the control group. Analysis of the four studies that included patients with extreme obstruction (FEV₁ or peak flow <35% of predicted at presentation) showed substantial improvement with ipratropium therapy (effect size 0.38, 95% CI: 0.09 to 0.67). In the five trials (1,186 patients) that studied the effect of ipratropium administration on hospital admissions, pooled results revealed that ipratropium reduced admission rates significantly (odds ratio 0.62, 95% CI: 0.44 to 0.88, P = 0.007).
CONCLUSIONS: The addition of ipratropium to beta-agonist therapy offers a statistically significant, albeit modest, improvement in pulmonary function, as well as a reduction in the rate of hospital admissions.
The role of ipratropium bromide in the emergency management of acute asthma exacerbation: A metaanalysis of randomized clinical trials
1999, Annals of Emergency Medicine
Study objective: This study was conducted to determine whether the addition of inhaled ipratropium to inhaled β-agonist therapy is effective in the treatment of adults with acute asthma exacerbation. Methods: Published reports of randomized, controlled trials assessing the use of ipratropium and β-agonists in asthma were identified by a search of the MEDLINE, EMBASE, CINAHL, Biological Abstracts on CD, the Cochrane Library, and Current Contents databases. Bibliographies from identified studies and from review articles were manually searched. Published and unpublished reports in English, French, and Italian were identified and assessed for inclusion in the metaanalysis. Randomized, double-blind, placebo-controlled trials were selected in which ipratropium was used as adjunctive therapy to β-agonists in adult patients with acute asthma exacerbation presenting to a hospital emergency department or similar acute care setting. Data were extracted independently by 2 reviewers. For eligible trials, the mean percent change in peak expiratory flow rate (PEFR), or forced expiratory volume in one second (FEV ₁ ), and their SDs were assessed in the ipratropium-treated and control groups. The effect of ipratropium on hospitalization rates and adverse effects were also analyzed. Results: Data from 10 studies, reporting on a total of 1,377 patients with asthma, were pooled using a weighted average method. Compared with placebo, the use of ipratropium was associated with a pooled 7.3% improvement in FEV ₁ (95% confidence interval [CI] 3.8% to 10.9%), corresponding to an absolute improvement in FEV ₁ in the ipratropium/ β-agonist group, which was 100 mL (95% CI 50 to 149 mL) above that seen for the group that received β-agonist without ipratropium. Similarly, the pooled estimate of treatment effect in trials that reported data as PEFR was 22.1% (95% CI 11.0% to 33.2%), corresponding to an absolute peak expiratory flow improvement of 32 L/min (95% CI 16 to 47 L/min) in favor of the ipratropium/ β-agonist combination group. When these data were combined using effect size as a common measure, the use of ipratropium was associated with a summary effect size of .38 (95% CI .27 to .48). Effect sizes were negatively correlated with baseline mean expiratory flows, suggesting that studies enrolling patients with more severe airflow obstruction showed greater absolute benefits of combination bronchodilator therapy. For the 3 trials reporting hospital admission data (n=1,031), patients receiving ipratropium had a relative risk of hospitalization of .73 (95% CI .53 to .99). The use of ipratropium was not associated with any severe adverse effects when used in conjunction with β ₂ -agonists. Conclusion: There is a modest statistical improvement in airflow obstruction when ipratropium is used as an adjunctive treatment to β ₂ -agonists for the treatment of acute asthma exacerbation. Although the clinical significance of this improvement in airflow obstruction remains unclear, it would seem reasonable to recommend the use of combination ipratropium/ β-agonist therapy in acute adult asthmatic exacerbations, since the addition of ipratropium seemed to provide physiologic evidence of benefit without risk of adverse effects.[Stoodley RG, Aaron SD, Dales RE: The role of ipratropium bromide in the emergency management of acute asthma exacerbation: A metaanalysis of randomized clinical trials. Ann Emerg Med July 1999;34:8-18.]
Additive effect of oxitropium bromide in combination with inhaled corticosteroids in the treatment of elderly patients with chronic asthma
1999, Allergology International
The efficacy of the addition of inhaled oxitropium bromide in combination with inhaled corticosteroids in the treatment of elderly asthmatic patients whose asthma is not well controlled was evaluated. A randomized, open-label cross-over trial comparing 4-week treatment periods with and without regular inhalation of 200 μg of oxitropium bromide four times per day was performed. Twenty-four patients (mean age ± SD: 62 ± 7 years) completed the study. The dose of beclomethasone dipropionate in this patient group was 1300 ± 800 μg/day. Forced expiratory volume in 1 second (FEV₁) was significantly improved after treatment with regular inhalation of oxitropium bromide when compared with FEV₁ after treatment without oxitropium (1.73 ± 0.60 vs 1.63 ± 0.68). Both morning and evening peak expiratory flow rates were significantly greater during the treatment period with regular inhalation of oxitropium bromide. The score for dyspnea/chest tightness was also significantly improved during the oxitropium bromide period. There was no statistically significant improvement in forced vital capacity, scores for other symptoms or the frequency of rescue inhalation of fenoterol. The results of this study demonstrated that the addition of regular inhalation of oxitropium bromide is beneficial in elderly asthmatics whose asthma is not well controlled, even when treated with high-dose inhaled steroids.

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: Manuscript received August 2; revision accepted December 3.

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Chest

Clinical InvestigationsEffects of Ipratropium Bromide Nebulizer Solution with and without Preservatives in the Treatment of Acute and Stable Asthma

Section snippets

Patients

Results

Discussion

ACKNOWLEDGMENTS

Chest

Am J Med

Lancet

A comparison of the bronchodilator activity of Sch 1000 and salbutamol

J Allergy Clin Immunol

Influence of age on response to ipratropium and salbutamol in asthma

Thorax

Responses to the sequential administration of salbutamol and ipratropium bromide during recovery from acute severe asthma

Thorax

Nebulised ipratropium in the treatment of acute asthma

Chest

Adverse reaction to ipratropium bromide

BMJ

Adverse reaction to ipratropium bromide

BMJ

Bronchoconstriction induced by ipratropium bromide in asthma: relation to hypotonicity

BMJ

Bronchoconstriction induced by ipratropium bromide: relation to bromide ion

BMJ

Clinical Investigations
Effects of Ipratropium Bromide Nebulizer Solution with and without Preservatives in the Treatment of Acute and Stable Asthma