Addition of anticholinergic solution prolongs bronchodilator effect of beta 2 agonists in patients with chronic obstructive pulmonary disease. Usefulness of inhaled magnesium sulfate in the coadjuvant management of severe asthma crisis in an emergency department. In chronic obstructive pulmonary disease, a combination of ipratropium and albuterol is more effective than either agent alone. An 85-day multicenter trial. COMBIVENT Inhalation Aerosol Study Group. Severe exacerbations of COPD and asthma. Incremental benefit of adding ipratropium to usual therapy. Nebulized anticholinergic and sympathomimetic treatment of asthma and chronic obstructive airways disease in the emergency room. Slowing the deterioration of asthma and chronic obstructive pulmonary disease observed during bronchodilator therapy by adding inhaled corticosteroids. A 4-year prospective study. A comparison of the effects of ipratropium bromide and metaproterenol sulfate in acute exacerbations of COPD. Asthma control during and after cessation of regular beta 2-agonist treatment. Routine nebulized ipratropium and albuterol together are better than either alone in COPD. The COMBIVENT Inhalation Solution Study Group.
A randomized, double-blind placebo-controlled clinical trial was designed to assess the safety, efficacy, and duration of the bronchodilation resulting from the addition of 500 micrograms of ipratropium bromide (Atrovent; Boehringer Ingelheim, CT) inhalation solution to standard small volume nebulizer treatments with 2.5 mg albuterol inhalation solution. A total of 195 patients (63% men, average age 64 years) with > 10 pack-year smoking histories and stable, moderate-to- severe chronic obstructive pulmonary disease (COPD; forced expiratory volume in 1 second [FEV1] 1.02 liter, 38.8% predicted) from eight university-affiliated chest clinics in seven U.S. cities were enrolled into the study. Asthma, rhinitis, and eosinophilia were exclusions, as was daily use of > 10 mg of prednisone (or 20 mg on alternate days). There was a 2-week stabilization period during which the patients were instructed in the use of the small volume nebulizers, which they used three times daily with albuterol alone. They were asked to keep daily logs of peak flow rates, pulmonary symptoms, and additional medication usage. On their test day 1 the subjects came to the pulmonary function laboratory having been off theophylline for 24 hours and beta 2-agonists for 12 hours and performed a baseline spirometry. They then received their morning small volume nebulizer treatment of albuterol to which was added either 500 micrograms if ipratropium bromide or a saline placebo. Spirometry was repeated at 15, 30, and 60 minutes, and then hourly for 8 hours. Subjects then took home a 2-week supply of albuterol and test drug for thrice daily use in their small volume nebulizer. They were evaluated for pulmonary symptoms and adverse effects every 14 days. The 8-hour spirometry was repeated on test day 43 and finally on test day 85. Primary data evaluated were the peak increase in FEV1 and the area between the FEV1 baseline value and the 8-hour FEV1 curve. Similar calculations were made for forced vital capacity (FVC) and 25-75% forced expiratory flow (FEF25-75%). On test day 1 the peak increase in FEV1 for the ipratropium bromide + albuterol subjects was 26% greater than those on placebo + albuterol (p < 0.003). The area under the 8-hour FEV1 curve was 64% greater in those given ipratropium bromide on test day 1 (p < 0.0002). Similar increases were seen in FVC and FEF25-75%. The peak improvements in FEV1 and FVC with the addition of ipratropium bromide to albuterol were maintained on test days 43 and 85. Considering the safety and efficacy profiles of this combination, the data would suggest that ipratropium bromide inhalation solution should be considered first-line therapy for those patients with COPD requiring small volume nebulizer treatments. Treatment of severe asthma may be difficult despite the use of several medications including parenteral corticosteroids. Intravenous magnesium sulfate (MgSO(4)) is one ancillary drug for severe crisis; its inhaled use is controversial.
                To evaluate the usefulness of inhaled MgSO(4) compared to placebo in improving lung function, oxygen saturation, and reducing hospital admission as an adjunct to standard treatment in severe asthma crisis.
                We conducted a placebo-controlled, double-blind clinical trial with asthmatic patients >18 years of age with asthmatic crisis and FEV(1)<60% of predicted (%p). All subjects received 125 mg of IV methylprednisolone followed by nebulization with the combination of albuterol (7.5mg) and ipratropium bromide (1.5mg) diluted in 3 ml of isotonic saline solution (as placebo) or 3 ml (333 mg) of MgSO(4). After 90 min, subjects with FEV(1)<60%p or SpO(2)<88% or persistent symptoms were admitted to the emergency department (ED).
                We included 30 patients per group who were similar at baseline. The MgSO(4) group showed higher post-bronchodilator (post-BD) FEV(1)%p (69+/-13 vs. 61+/-12, p<0.014) and SpO(2) (92+/-4 vs. 88+/-5%, p<0.006) than the placebo group. Fewer treated patients were admitted to the ED (5 vs. 13) (p<0.047), with relative risk (RR) of 0.26 (95% CI 0.079-0.870).
                Adding inhaled MgSO(4) treatment to standard therapy in severe asthma crisis improves FEV(1)%p and SpO(2) post-BD and reduces the rate of ED admissions.
                Copyright 2010 Elsevier Ltd. All rights reserved. Combination bronchodilator therapy for chronic obstructive pulmonary disease (COPD) is available widely throughout the world except in North America. Previous studies have yielded conflicting results regarding the advantages of combining anticholinergic therapy with sympathomimetic therapy in COPD. We report the results of a 12-week prospective, double-blind, parallel-group evaluation of the use of the following: albuterol, a beta-adrenergic agent; ipratropium, an anticholinergic agent; or a combination of the two, administered by metered-dose inhaler to patients with moderately severe stable COPD. Following baseline studies, 534 patients were given one of the three test bronchodilator preparations to be used at home four times daily in addition to oral theophylline and corticosteroids as required. The doses of the latter two drugs were kept stable. Subjects were tested on days 1, 29, 57, and 85. Analysis of 1-s forced expiratory volume (FEV1) curves on those test days indicated that the combination was superior to either single agent alone in peak effect, in the effect during the first 4 h after dosing, and in the total area under the curve of the FEV1 response. The mean peak percent increases in FEV1 over baseline on the four test days were 31 to 33 percent for the combination, 24 to 25 percent for ipratropium, and 24 to 27 percent for albuterol. The differences between the combination and its components were statistically significant on all test days. The AUC0-4 means for the combination were 21 to 44 percent greater than the ipratropium means and 30 to 46 percent greater than the albuterol means. Similar changes were noted in the forced vital capacity curves. Symptom scores did not change over time and did not differ among the treatment groups. We conclude that the combination of ipratropium and albuterol, when given by metered-dose inhaler to patients with COPD, is more effective than either of the two agents alone. The advantage of the combination is apparent primarily during the first 4 h after administration. The availability of combination therapy by metered-dose inhaler should help to improve patient compliance. Single dose studies have assessed the utility of ipratropium bromide alone or with beta agonists in the short- and long-term management of chronic obstructive lung disease and asthma. We performed a randomized, double-blind trial to assess the incremental benefit over 24 hours of adding ipratropium vs placebo to a standardized regimen of medications commonly used in the acute and subsequent hospital management of COPD and asthma. Sixty-eight subjects received nebulized salbutamol, intravenous methylprednisolone, intravenous aminophylline, and antibiotics and were randomized to receive either 80 micrograms of ipratropium or placebo via metered dose inhaler and spacing device with each salbutamol treatment (6 to 8 times per day). Among the 50 patients who completed the study, there were no significant differences between ipratropium and placebo groups with respect to baseline FEV1, FVC, and PaCO2. The improvement of FEV1 from baseline to 24 hours was 294 (SD = 568) ml in the ipratropium group vs 393 (SD = 622) ml in placebo group. Adjusting FEV1 by age, gender, and smoking did not significantly alter the findings. Those with an admission diagnosis of asthma showed larger 24 hour FEV1 responses (487 ml in ipratropium vs 801 ml in placebo) than those with COPD (149 ml ipratropium vs 102 ml in placebo). However, within these two strata, there were no significant differences in FEV1 improvement between ipratropium and placebo groups. This study suggests that if ipratropium is used in the initial emergency treatment of COPD or asthma, it could safely be discontinued by 24 hours in order to reduce the cost and complexity of therapy. The effectiveness of nebulized anticholinergic and sympathomimetic regimens was evaluated in a double-blind study of 199 patients with acute airways obstruction. Patients were assigned to one of three treatment regimens according to a randomized schedule: 0.5 mg of ipratropium bromide, 1.25 mg of fenoterol hydrobromide, and 0.5 mg of ipratropium plus 1.25 mg of fenoterol. In 148 patients with acute exacerbations of asthma (mean one-second forced expiratory volume, 1.18 +/- 0.64 liters), all three regimens produced significant improvement in one-second forced expiratory volume (p less than 0.001). The greatest improvement followed treatment with the ipratropium-fenoterol combination (0.53 +/- 0.40 liters at 45 minutes; 0.57 +/- 0.51 liters at 90 minutes) and was significantly greater than that following either ipratropium alone (p less than 0.001) or fenoterol alone (p less than 0.05). In 51 patients with acute exacerbations of chronic obstructive pulmonary disease (mean one-second forced expiratory volume, 0.67 +/- 0.29 liter), each regimen produced significant improvement in one-second forced expiratory volume at both 45 and 90 minutes (for all, p less than 0.05), but there was no significant difference among the three treatment regimens. It is concluded that, in patients with acute asthma, combination therapy with sympathomimetic and anticholinergic agents is more efficacious than either one alone. In patients with acute exacerbations of chronic obstructive pulmonary disease, although either sympathomimetic or anticholinergic therapy provides bronchodilatation, no further benefit could be demonstrated from combination therapy. To determine if deterioration in patients with asthma or chronic obstructive pulmonary disease (COPD) during bronchodilator therapy could be slowed by additional treatment with an inhaled corticosteroid.
                A 4-year prospective study.
                Twenty-nine general practices in the catchment area of the University of Nijmegen, Nijmegen, the Netherlands.
                The study included 56 patients (28 with asthma and 28 with COPD) who showed an annual decrease in the forced expiratory volume in 1 second (FEV1) of at least 80 mL in combination with at least two exacerbations per year during bronchodilator therapy alone. Forty-eight patients completed the study.
                During the first 2 years of treatment, patients received only bronchodilator therapy (salbutamol, 400 micrograms, or ipratropium bromide, 40 micrograms). During years 3 and 4, they received additional treatment with beclomethasone dipropionate, 400 micrograms two times daily.
                Prebronchodilator FEV1 increased 458 mL/y (95% CI, 233 to 683 mL/y) during the first 6 months of beclomethasone treatment; FEV1 then decreased 102 mL/y (CI, 57 to 147 mL/y) during months 7 to 24. The annual decline in FEV1 during beclomethasone treatment was less than the decline of 160 mL/y seen before beclomethasone therapy (difference, 58 mL/y; 95% CI, 2 to 87 mL/y). Only in patients with asthma did beclomethasone treatment improve bronchial hyperresponsiveness (assessed by determining the concentration of histamine that provoked a 20% decrease in FEV1 [PC20]) by 3.0 doubling doses per year (95% CI, 0.8 to 5.2 doses per year). Beclomethasone treatment was associated with improvement in peak expiratory flow rate, alleviation of symptoms, and a decrease in the number of exacerbations in both patient groups.
                Adding beclomethasone, 800 micrograms daily, slowed the unfavorable course of asthma or COPD seen with bronchodilator therapy alone. This effect was most evident in asthmatic patients. Thirty-two patients presenting with acute exacerbations of chronic obstructive pulmonary disease were entered into the following double-blind, crossover study. First (time 0), patients inhaled either ipratropium bromide (54 micrograms) or metaproterenol sulfate (1.95 mg) via a metered dose inhaler (MDI) attached to a device (Inspirease) (phase 1). After 90 minutes, they inhaled whichever of the two medications they had not received in phase 1. This is referred to as phase 2. Pulmonary function (FEV1 and FVC) was measured at time 0, and at 30, 60, and 90 minutes following phase 1 treatment, and at 30, 60, and 90 minutes following phase 2 treatment (120, 150, and 180 minutes from the start of the study). Arterial blood gas samples (n = 20) were obtained at entry into the study and 30 and 90 minutes after phase 1 medication. The groups did not differ in age, degree of airway obstruction, hypoxemia, or theophylline usage at the start of the study. In phase 1, at 90 minutes, pulmonary function in both groups significantly and similarly improved. For ipratropium, FEV1 improved from 0.62 +/- 0.08 L to 0.88 +/- 0.11 L (p less than 0.01) and for metaproterenol FEV1 improved from 0.69 +/- 0.06 to 0.92 +/- 0.09 L (p less than 0.01). There was no further improvement with phase 2 treatment for either group. Thirty minutes after inhaling ipratropium, there was a small but significant rise in PO2 (5.8 +/- 3.0 mm Hg; p less than 0.05) while metaproterenol inhalation resulted in a 6.2 +/- 1.2 mm Hg decline in PO2 (p less than 0.05). These changes were not sustained at 90 minutes. We concluded that for acute exacerbations of COPD, both ipratropium and metaproterenol are effective medications when administered via an MDI attached to a device (Inspirease). However, ipratropium may be a safer choice as it initially did not cause a decline in blood oxygenation. It has been suggested that regular treatment with high doses of beta 2-agonists might result in poorer control of asthma and increased bronchial responsiveness. We have examined change in FEV1 (delta FEV1), bronchial reactivity, peak expiratory flow (PEF), and symptoms during and after 3 wk of regular treatment with a relatively low dose of albuterol and broxaterol, a new beta 2-agonist. Eleven subjects 18 to 50 yr of age with mild asthma inhaled albuterol (200 micrograms), broxaterol (400 micrograms), or placebo three times a day for 3 wk with a 2- to 4-wk run-in/washout period between treatments. Ipratropium bromide was allowed for symptomatic relief. The PD20 (dose of histamine causing a 20% fall in FEV1) was measured before and 11, 35, and 59 h after cessation of treatment and a bronchodilator dose-response study before and 83 h after cessation of treatment. Change from baseline after albuterol and broxaterol are compared with change after placebo. Diurnal change in PEF (amplitude % mean) increased during treatment with albuterol by 6.5% (95% CI, 1.7-12.3; p < 0.02) mainly because of a fall in morning PEF. Cessation of treatment with both beta 2-agonists was associated with a fall in FEV1 and PD20 compared with placebo.(ABSTRACT TRUNCATED AT 250 WORDS) We compared the long-term safety and efficacy of the combination ipratropium bromide (IB) and albuterol sulfate (ALB) inhalation solution with that of each separate component using three-times-daily administration.
                Using a parallel design, we randomized patients to receive 3.0 mg ALB, 0.5 mg IB, or the combination by small-volume nebulizer (SVN) for 85 days. Subjects were allowed to use up to two extra doses of study medication daily for control of symptoms on an as-needed basis. The main efficacy evaluation was the acute pulmonary function response to an aerosol of the maintenance study medication over the course of the investigation. Physician global evaluation, subject quality of life assessments, COPD symptom scores, and twice-daily peak expiratory flow rate (PEFR) were also assessed over the study period.
                Twenty-five centers participated in the investigation.
                We studied 652 patients with moderate to severe COPD.
                Over the course of the study, the acute spirometric response and evening PEFR values with the SVN combination of IB plus ALB were statistically significantly better compared to ALB or IB alone. The quality of life scores, physician global evaluations, symptom scores, and morning PEFR scores were unchanged over the duration of the study in all treatment groups. There was no significant difference in adverse events in the three treatment groups.
                In patients with COPD, maintenance SVN therapy with IB and ALB provides better bronchodilation than either therapy alone without increasing side effects.
There is currently no good evidence that inhaled MgSO4 can be used as a substitute for inhaled β2-agonists. When used in addition to inhaled β2-agonists (with or without inhaled ipratropium), there is currently no overall clear evidence of improved pulmonary function or reduced hospital admissions. However, individual study results from three trials suggest possible improved pulmonary function in those with severe asthma exacerbations (FEV1 less than 50% predicted). Heterogeneity among trials included in this review precludes a more definitive conclusion. Further studies should focus on inhaled MgSO4 in addition to the current guideline treatment for acute asthma (inhaled β2 -agonist and ipratropium bromide). As the evidence suggests that the most effective role of nebulised MgSO4 may be in those with severe acute features and this is where future research should be focused. A set of core outcomes needs to be agreed upon both in adult and paediatric studies to allow improved study comparison in future.