Anticholinergic therapy for acute asthma in children.

BACKGROUND: Inhaled anticholinergics as single agent bronchodilators (or in combination with beta(2)-agonists) are one of the several medications available for the treatment of acute asthma in children. OBJECTIVES: To determine the effectiveness of only inhaled anticholinergic drugs (i.e. administered alone), compared to a control in children over the age of two years with acute asthma. SEARCH METHODS: The Cochrane Register of Controlled Trials (CENTRAL), and the Cochrane Airways Group Register of trials were searched by the Cochrane Airways Group. The latest search was performed in April 2011. SELECTION CRITERIA: We included only randomised controlled trials (RCTs) in which inhaled anticholinergics were given as single therapy and compared with placebo or any other drug or drug combinations for children over the age of two years with acute asthma. DATA COLLECTION AND ANALYSIS: Two authors independently selected trials, extracted data and assessed trial quality. MAIN RESULTS: Six studies met the inclusion criteria but were limited by small sample sizes, various treatment regimes used and outcomes assessed. The studies were overall of unclear quality. Data could only be pooled for the outcomes of treatment failure and hospitalisation. Other data could not be combined due to divergent outcome measurements. Meta-analysis revealed that children who received anticholinergics alone were significantly more likely to have treatment failure compared to those who received beta(2)-agonists from four trials on 171 children (odds ratio (OR) 2.27; 95% CI 1.08 to 4.75). Also, treatment failure on anticholinergics alone was more likely than when anticholinergics were combined with beta(2)-agonists from four trials on 173 children (OR 2.65; 95% CI 1.2 to 5.88). Data on clinical scores/symptoms that were measured on different scales were conflicting. Individual trials reported that lung function was superior in the combination group when compared with anticholinergic agents used alone. The use of anticholinergics was not found to be associated with significant side effects. AUTHORS' CONCLUSIONS: In children over the age of two years with acute asthma exacerbations, inhaled anticholinergics as single agent bronchodilators were less efficacious than beta(2)-agonists. Inhaled anticholinergics were also less efficacious than inhaled anticholinergics combined with beta(2)-agonists. Inhaled anticholinergic drugs alone are not appropriate for use as a single agent in children with acute asthma exacerbations.

Use of ozone-depleting substances; removal of essential-use designation (flunisolide, etc.). Final rule.

The Food and Drug Administration (FDA), after consultation with the Environmental Protection Agency (EPA), is amending FDA's regulation on the use of ozone-depleting substances (ODSs) in self-pressurized containers to remove the essential-use designations for flunisolide, triamcinolone, metaproterenol, pirbuterol, albuterol and ipratropium in combination, cromolyn, and nedocromil used in oral pressurized metered-dose inhalers (MDIs). The Clean Air Act requires FDA, in consultation with the EPA, to determine whether an FDA-regulated product that releases an ODS is an essential use of the ODS. FDA has concluded that there are no substantial technical barriers to formulating flunisolide, triamcinolone, metaproterenol, pirbuterol, albuterol and ipratropium in combination, cromolyn, and nedocromil as products that do not release ODSs, and therefore they will no longer be essential uses of ODSs as of the effective dates of this rule. MDIs for these active moieties containing an ODS may not be marketed after the relevant effective date.

High degree atrioventricular block with ventricular asystole in a case of dengue fever.

Cardiac rhythm abnormalities have been uncommonly observed in dengue fever and most of them have been reported in children. We discuss a 30-year-old female with dengue fever, who presented with repeated symptomatic episodes of high degree atrioventricular block with ventricular asystole, which responded to intravenous atropine and oral orciprenaline without recurrence on 6 months follow-up.

Pharmacological Provocation of Outflow-Tract Tachycardia in a Patient With Brugada Syndrome.

We present a case of a symptomatic patient with Brugada syndrome, who had sustained right ventricular outflow tract tachycardia after pronounced exercise-induced ST segment elevation in V1 and V2. In electrophysiological study he developed right ventricular outflow tract tachycardia provoked by combined infusion of ajmaline and orciprenaline. After ablation no further arrhythmia was provoked by pharmacological stimulation.

Is electrical stimulation during administration of catecholamines required for the evaluation of success after ablation of atrioventricular node re-entrant tachycardias?

OBJECTIVES: The purpose of this study was to answer the question of whether stimulation after administration of catecholamines is mandatory for identifying unsuccessful ablations of atrioventricular node re-entrant tachycardia (AVNRT). BACKGROUND: The success of radiofrequency (RF) catheter ablation in AVNRT is confirmed in many centers by noninducibility of tachycardias during stimulation after the administration of catecholamines. METHODS: A total of 131 patients (81 women and 50 men; mean age 53.6 +/- 13.7 years [range 20 to 77]) were studied. Electrical stimulation was performed without and with the beta-adrenergic amine Orciprenaline (metaproterenol) before and after RF catheter ablation. RESULTS: In 100 patients (76.3%; confidence interval [CI] 68.1% to 83.3%) an AVNRT was inducible without administration of Orciprenaline. Thirty minutes after the initially successful ablation in 95 patients, tachycardia was inducible in none of these patients, not even after Orciprenaline administration. In the 31 patients (23.7%; CI 16.7% to 31.9%) in whom there was no tachycardia inducible before ablation, Orciprenaline was given, and the stimulation protocol was repeated. In only five patients (3.8%; CI 1.3% to 8.7%) was there still no tachycardia inducible. After an initially successful ablation in the 26 patients who had inducible tachycardias with Orciprenaline before ablation, no tachycardia could be re-induced. After Orciprenaline, the tachycardia was inducible again in only one patient. CONCLUSIONS: Only patients who require catecholamines for tachycardia induction before ablation need catecholamines for control of the success of the ablation of AVNRT.

An adrenergic drug in depression.

It has been suggested that depression is a disease of cholinergic dominance and since the beta-adrenergic blocking drug propranolol hydrochloride can cause depression, there arises the possibility that a beta-adrenergic stimulant could benefit the condition. For ethical reasons, the adrenergic drug metaproterenol sulfate was combined with chlordiazepoxide hydrochloride and compared to placebo and chlordiazepoxide in a formal double-blind trial. However, the results did not show any advantage for the addition of metaproterenol either in respect of enhanced antidepressant effect or a reduced incidence, nature, or severity of side-effects.

Response to inhaled beta-agonist in a patient receiving beta-adrenergic blockers.

A 52-year-old man receiving long-term hemodialysis and a beta-adrenergic blocker for hypertension had symptoms of acute bronchospasm when exposed to a new hemodialyzer. Resistant to two doses of subcutaneous epinephrine (1 mL of 1:1000 dilution) and one intravenous dose of aminophylline (250 mg), the bronchospasm was rapidly relieved by metaproterenol sulfate given by inhalation one hour later.

Aerosol bronchodilator delivery methods. Relative impact on pulmonary function and cost of respiratory care.

Thirty-six acutely III, hospitalized patients with acute exacerbations of obstructive airway disease and a greater than 10% increase in forced expiratory volume in 1 s after administration of aerosolized bronchodilator were randomized to receive either metaproterenol sulfate delivered by updraft-compressor nebulization (UDN) or terbutaline sulfate delivered by metered-dose inhaler (MDI) with a spacer. Serial analyses of pulmonary function measurements were performed with the use of 95% confidence intervals for the percentage response ratios of MDI to UDN. The response to MDI was at least equivalent to that of UDN, and MDI use was associated with no prolongation of hospital stay. Equivalent bronchodilation was achieved with MDI therapy with a lower daily charge for therapy for each patient and less respiratory therapist time. In hospitalized bronchodilator-responsive patients with acute exacerbations of obstructive airway disease, the MDI/spacer combination is the preferred approach when the status of the patient allows its use.

Interpretation of positive results of a methacholine inhalation challenge and 1 week of inhaled bronchodilator use in diagnosing and treating cough-variant asthma.

BACKGROUND: In diagnosing cough due to asthma, methacholine chloride inhalation challenge (MIC) interpreted in a traditional fashion has been shown to have positive predictive values from 60% to 82%. OBJECTIVE: To determine whether any features of positive results of an MIC or the results of a 1-week trial of inhaled beta-agonist therapy were helpful in predicting when the cough was due to asthma. METHODS: The study design was a prospective, randomized, double-blind, placebo-controlled, crossover format performed in adult, nonsmoking subjects, who were referred for diagnosis and treatment of chronic cough. The subjects had no other respiratory complaints or medical conditions for which they were taking medications, the results of baseline spirometry and chest roentgenograms were normal, and the results of MIC were positive. After obtaining baseline data, including MICs on 2 separate days, objective cough counting, and self-assessment of cough severity using a visual analog scale, subjects were randomized to receive 2 inhalations (1.3 mg) of metaproterenol sulfate or placebo by metered dose inhaler attached to a spacer device every 4 hours while awake. At 1 week, data identical to baseline were collected, and subjects received the other metered dose inhaler for 7 days. At 1 week, data identical to baseline were collected. After completion of the protocol, subjects were followed up in the clinic to observe the final response of the cough to specific therapy. RESULTS: Based on the disappearance of the cough with specific therapy, the cough was due to asthma in 9 of 15 subjects and nonasthma in 6 of 15 subjects. Baseline data were similar between groups. With respect to MICs, there were no significant differences between groups in the cumulative dose of methacholine that provoked a 20% decrease in forced expiratory volume in 1 second from the postsaline baseline value (PD20 values), slopes of dose-response curves, and maximal-response plateaus. Cough severity significantly improved after 1 week of metaproterenol use compared with the severity of the cough at baseline (P = .03) and with placebo (P = .02) only in subjects with asthma. CONCLUSIONS: No matter how the results are analyzed, positive MIC results, without observing response to therapy, are only consistent with asthma as the cause of the cough. The results are only diagnostic of asthma when they are followed by a favorable response to asthma therapy. After 1 week of inhaled beta-agonist, only the cough due to cough-variant asthma is significantly better.

Bronchodilating effect of terbutaline aerosol.

We compared the efficacy of terbutaline with that of metaproterenol, isoproterenol, and placebo aerosols in 16 asthmatic patients. Terbutaline, metaproterenol, and isoproterenol produced equivalent improvements in flow rates. At 5 hr, the effect of terbutaline on tests of small airways, FEF25%--75%, and FEF50%, was greater (p less than 0.05) than that of metaproterenol and isoproterenol. Terbutaline produced no significant change of heart rate or blood pressure.

Tissue protein turnover in animals treated with the mixed beta-agonist metaproterenol: influence of dose, route and pattern of administration.

beta-Adrenergic agonists have been shown to increase protein deposition as a result of changes in the balance between protein synthesis and degradation rates. The aim of this study is to investigate the effect of the treatment with the non-selective beta-adrenergic agonist, metaproterenol, on protein metabolism in rats as well as the influence of the route and pattern of administration. A short- and long-term experimental trial were carried out. After the short-term treatment with the beta-agonist (1 mg/kg), neither protein nor nucleic acids were affected in liver or gastrocnemious muscle, while cathepsin A activity, an index of protein degradation, significantly increased in muscle. However, cathepsin A activity was reduced in muscle by the oral administration during 21 days of metaproterenol (2 ppm/day), but not by the subcutaneous injections (0.1 mg/kg/day). On the other hand, RNA/DNA, an index of protein synthesis capacity, and protein/DNA, an indicator of cell size, significantly diminished in muscle after the subcutaneous long-term treatment but did not change in the liver of treated rats. Our study has demonstrated a different outcome of a mixed beta-adrenergic agonist on protein metabolism depending on the duration of the treatment and the route of administration.

Comparison of oral aminophylline and aerosol metaproterenol in asthma.

The bronchodilator efficacy of oral aminophylline and aerosol metaproterenol was compared in 18 asthmatic patients in a stable clinical condition. Treatment consisted of four regimens in a double-blind random sequence on four different days after withholding bronchodilators: (1) the administration of aminophylline tablets, 0.4 to 0.6 g, orally, (2) 3 puffs of aerosol metaproterenol administered in a sequential manner, (3) a combination of both, (4) placebos. Both oral aminophylline and aerosol metaproterenol produced significant bronchodilatation measured by forced expiratory volume in 1 second (FEV1). After the administration of aerosol metaproterenol, there was a more prompt and larger improvement in FEV1 than after the administration of aminophylline (p less than 0.01). The combined therapy produced a response which was larger, but not significantly, than the effect of metaproterenol. Side effects were frequent after the administration of aminophylline but absent after aerosol metaproterenol. The advantages of the aerosol adrenergic agonists are the prompt onset of action and efficacy, small dosage preferentially delivered to the bronchial tree and lack of side effects.

Use of ipratropium bromide in asthma. Results of a multi-clinic study.

A multi-center, double-blind, 90-day study compared an ipratropium bromide metered-dose inhaler (40 microgram four times a day) with a metaproterenol metered-dose inhaler (1,500 micrograms four times a day) in 164 patients with asthma; of the 144 patients who completed the study, 71 received ipratropium and 73 received metaproterenol. Our results suggest that both drugs were equally effective bronchodilators. Although the shape of the pulmonary function response curves suggested that ipratropium has different bronchodilator kinetics than metaproterenol (in that it has a slower onset of action and a more prolonged duration), comparison of the areas under the curves for the two drugs showed that there was no statistical difference between ipratropium or metaproterenol. The only significant side effects noted with ipratropium were cough and exacerbation of symptoms; no anticholinergic side effects were noted.

"Noninvasive" oral treatment of asthma in the emergency room.

One hundred forty consecutive patients with acute asthmatic episodes presenting to the emergency room were studied prospectively to assess the efficacy of oral therapy. After the emergency room staff was oriented to the pharmacologic action of hydroalcoholic elixir of theophylline, oral terbutaline, and a metered-dose hand-held nebulizer (metaproterenol), use of oral therapy as initial therapy rose from 12 percent to 76 percent (p = 0.005). More than half of these patients were discharged without receiving any of the traditional more invasive therapies of subcutaneous epinephrine, intravenous hydrating fluids with aminophylline, and machine-delivered sympathomimetic aerosols. Oral therapy did not substantially alter the total time spent in the emergency room. Only 4 percent treated with oral therapy required further treatment in the emergency room within 48 hours; 2 percent vomited after treatment. Oral therapy is safe and effective for most asthmatic patients presenting to the emergency room, as they generally are undermedicated with regard to theophyllines and sympathomimetic drugs. Use of oral therapy in the emergency room is a potent tool for educating asthmatic patients in the use of medication available for home use. The patients who require emergency room treatment despite being well-medicated at home (a small minority) need a higher level of care including intermittent positive-pressure breathing, corticosteroids, and often hospitalization.

Results of a multicenter study of nebulized inhalant bronchodilator solutions.

The efficacy, persistence of bronchodilator action, and safety of the quaternary ammonium anticholinergic agent, ipratropium bromide (500 microgram), and placebo were compared when each was added in solution form to the beta-adrenergic agonist solution, metaproterenol sulfate (15 mg), and administered three times daily for 12 weeks to a total of 213 patients with chronic obstructive pulmonary disease (COPD). Subjects had a mean forced expiratory volume in 1 second (FEV1) of approximately 1 liter (37% of predicted) and were permitted to use nonanticholinergic therapy for COPD throughout the trial. The study was a randomized, double-blind, 85-day, parallel-group, eight-center study. On a 3 test days, 1, 43, and 85, mean peak responses for FEV1 and forced vital capacity and mean area under the curve were significantly higher for the iprathropium bromide-metaproterenol combination than for metaproterenol only. Duration of action was also significantly longer for the combination therapy than for the beta-agonist alone on test days 1 and 43. Neither treatment regimen produced an demonstrable effect on daily morning peak expiratory flow rates, reported respiratory symptoms, or quality of life. Both treatment regimens were similarly well tolerated with a comparable frequency of adverse events. These results suggest that the combination of iprathropium bromide and metaproterenol inhalation solutions offers a potential therapeutic advantage to patients with symptomatic COPD over nebulized metaproterenol alone without the risk of increased side effects.

Effects of an inhaled bronchodilator on gas distribution and over-all ventilatory efficiency in patients with chronic obstructive pulmonary disease.

The effects of an inhaled bronchodilator on the distribution of inspired gas and over-all efficiency of ventilation were studied by the nitrogen washout technic in 16 patients with chronic obstructive pulmonary disease; three normal subjects and two patients with asymptomatic asthma (and normal spirometric values) were also studied. In normal and asthmatic subjects and in patients with chronic obstructive pulmonary disease and mild to moderate functional impairment, the nitrogen clearance did not vary significantly or showed changes suggesting less uniform gas distribution and reduced ventilatory efficiency. In most patients with advanced chronic obstructive pulmonary disease, the bronchodilator caused changes suggesting more uniform distribution of inspired gas and increased efficiency of ventilation. Multiple regression analysis showed that the behavior of the nitrogen clearance after treatment was also related to the response of the anatomic dead space. The effects of the bronchodilator varied with time. The results are consistent with the assumption that the changes in nitrogen clearance after bronchodilator therapy reflect the concourse of multiple factors, which may be expected to have favorable or unfavorable effects on the distribution of inspired gas and the efficiency of ventilation.

A multicenter study of nebulized bronchodilator solutions in chronic obstructive pulmonary disease.

A multicenter, 85-day, double-blind, randomized study was conducted to compare the effects of a single-dose and chronic inhalation of ipratropium bromide solution (500 micrograms) to the beta-adrenergic agonist metaproterenol (5% solution, 15 mg) in patients with chronic obstructive pulmonary disease (COPD). Patients were required to have a relatively stable, moderately severe COPD, forced expiratory volume in 1 second (FEV1) < 65% of predicted normal, FEV1 <70% of forced vital capacity (FVC), and a smoking history of > 10 pack-years. Following a 2-week baseline period, patients were randomized into either the ipratropium bromide (106 patients) or metaproterenol (107 patients) study groups. Pulmonary function testing was performed on days 1, 43, and 85. Secondary efficacy variables examined included peak expiratory flow rates, physician's global evaluation, quality of life, COPD symptom score, and use of concomitant medications. FEV1 was comparable between the two groups on day 1 (1.00 and 1.02 liters, ipratropium bromide vs metaproterenol, respectively; p = nonsignificant). The baseline FEV1 increased significantly in the ipratropium bromide group between day 1 and 43 by 10% (from 1.00 to 1.10 liters, p < 0.002) and remained 7% elevated on day 85 (1.07 liters) compared to day 1 (p < 0.02); it did not change in the metaproterenol group across all three test days. A clinically significant (> 15%) mean FEV1 response was observed on each of the 3 test days following drug inhalation in both treatment groups. The median duration of action was similar between groups (5 hours) on test day 1, but on day 85 the median duration for ipratropium bromide was r.5 hours compared to 3.0 hours for metaproterenol (p < 0.04). The secondary efficacy variables were uniformly better in the ipratropium bromide than the metaproterenol group. Side effects were infrequent and generally mild in both groups. These data suggest that the availability of a high-dose ipratropium bromide solution offers a safe and effective means of producing prolonged bronchodilation in patients with COPD.

Dose-response relationship of inhaled metaproterenol sulfate in preschool children with mild asthma.

The dose-response relationship of single doses of nebulized metaproterenol sulfate 5% inhalant solution was evaluated by placebo-controlled, parallel-group study of 30 children, aged 3 to 6 years old, with stable asthma. Total respiratory resistance, the primary variable used to assess response, was measured by the forced oscillation method for a period of 6 hours from the start of inhalation. When comparisons were made between metaproterenol sulfate and saline, only 0.01 and 0.02 mL/kg showed significant bronchodilation (P less than .05) in percent change from baseline and area under the curve. However, no significant differences were seen between these doses. Moreover, the effect was sustained for 3 hours with both higher doses. Minimal side effects were observed. Metaproterenol sulfate 5% inhalant solution at a dose of 0.01 mL/kg seems to be optimal to elicit significant and sustained bronchodilatory response in preschool children with mild asthma.

Comparison of albuterol and metaproterenol syrup in the treatment of childhood asthma.

This study compared the acute and chronic effects of albuterol syrup (2 mg) and metaproterenol syrup (10 mg) three times a day over 28 days in 65 children, aged 6 to 9 years, with mild to moderate asthma. Wright peak flow, symptom scores, and rescue medication use were recorded twice daily during the 28 days; the acute cardiopulmonary effects of these syrups were compared over 8 hours on treatment days 1 and 28. Albuterol syrup produced a significantly greater peak magnitude of bronchodilation than metaproterenol, 29% vs 20% above baseline, respectively, on treatment day 1. Albuterol syrup had a duration of action of at least 8 hours and produced greater bronchodilation than metaproterenol syrup from 2 to 8 hours on both treatment days 1 and 28. The chronotropic effect of metaproterenol was greater than that of albuterol at 1 to 1 1/2 hours postdose on treatment days 1 and 28. There was a trend toward higher morning and evening Wright peak flow measurements during 28 days of treatment in the albuterol group. Side effects of both drugs were comparable. These findings imply therapeutic advantages of albuterol syrup over metaproterenol syrup in currently recommended doses with respect to improvement in pulmonary function, chronotropic effects, and frequency of dosing required to maintain optimum bronchodilation over a 24-hour period.

Efficiency of air compressor-driven nebulizers.

Five different volumes of test solutions (1 to 3 ml) containing 15 mg of metaproterenol were placed in each of five different nebulizers. The time to complete nebulization and the amount of drug delivered varied considerably, depending upon the initial volume of solution placed in the nebulizer. Small volumes (1 ml) were almost totally retained in the nebulizer, whereas larger volumes (3 ml) took an unacceptably long time for nebulization. With vigorous agitation, a maximum of 53 to 72 percent of the dose left the nebulizer, but even less (34 to 59 percent) was delivered under simulated clinical conditions. When nebulization was synchronized with breathing, only 0.33 to 0.54 ml of solution (2 to 3.2 mg of metaproterenol) was delivered with 90 deep inhalations. If nebulization was continuous instead of intermittent during the time to take 90 breaths, the majority of the drug was nebulized to the atmosphere.