Overcoming beta-agonist tolerance: high dose salbutamol and ipratropium bromide. Two randomised controlled trials

Background

Asthmatics treated with long-acting beta-agonists have a reduced bronchodilator response to moderate doses of inhaled short acting beta-agonists during acute bronchoconstriction. It is not known if the response to higher doses of nebulised beta-agonists or other bronchodilators is impaired. We assessed the effect of long-acting beta-agonist treatment on the response to 5 mg nebulised salbutamol and to ipratropium bromide.

Methods

Two double-blind, placebo-controlled, crossover studies of inhaled formoterol 12 μg twice daily in patients with asthma. High-dose salbutamol: 36 hours after the last dose of 1 week of formoterol or placebo treatment, 11 subjects inhaled methacholine to produce a 20% fall in FEV₁. Salbutamol 5 mg was then administered via nebuliser and the FEV₁ was monitored for 20 minutes. Ipratropium: 36 hours after the last dose of 1 week of formoterol or placebo treatment, 11 subjects inhaled 4.5% saline to produce a 20% fall in FEV₁. Salbutamol 200 μg or ipratropium bromide 40 μg was then inhaled and the FEV₁ was monitored for 30 minutes. Four study arms compared the response to each bronchodilator after formoterol and placebo. Analyses compared the area under the bronchodilator response curves, adjusting for changes in pre-challenge FEV₁, dose of provocational agent and FEV₁ fall during the challenge procedure.

Results

The response to nebulised salbutamol was 15% lower after formoterol therapy compared to placebo (95% confidence 5 to 25%, p = 0.008). The response to ipratropium was unchanged.

Conclusion

Long-acting beta-agonist treatment induces tolerance to the bronchodilator effect of beta-agonists, which is not overcome by higher dose nebulised salbutamol. However, the bronchodilator response to ipratropium bromide is unaffected.     

Effect of fenoterol, ipratropium bromide and their combination--Berodual--on pulmonary ventilation in patients with asthma

The study aimed at evaluating FVC, FEV1, and FMF25-75% following and inhalation of fenoterol, ipratropium bromide and Berodual in 10 patients with the bronchial asthma. Berodual may be inhaled directly from the metered dose inhaler or with added tube spacer. Spirometry was performed after a single deep inspiration of each drug in the consecutive days, and after 5, 15, 30 and 60 minutes as well as 2, 3, 4, and 5 hours following the inhalation. The differences at each time point were compared with baseline values and expressed as percentage of the increase. The obtained results were analysed statistically. It was shown that bronchodilatory action of Berodual, being both beta 2-agonist and anticholinergic agent, is the most pronounced. The highest values of the measured spirometric parameters followed Berodual inhalation with the aid of tube spacer but the differences compared with Berodual applied with the metered dose inhaler were not statistically significant.     

Internal medicine: use of ipratropium bromide in chronic obstructive pulmonary disease

The Scientific Board of the California Medical Association presents the following inventory of items of progress in internal medicine. Each item, in the judgment of a panel of knowledgeable physicians, has recently become reasonably firmly established, both as to scientific fact and important clinical significance. The items are presented in simple epitome, and an authoritative reference, both to the item itself and to the subject as a whole, is generally given for those who may be unfamiliar with a particular item. The purpose is to assist busy practitioners, students, research workers or scholars to stay abreast of these items of progress in internal medicine that have recently achieved a substantial degree of authoritative acceptance, whether in their own field of special interest or another.The items of progress listed below were selected by the Advisory Panel to the Section on Internal Medicine of the California Medical Association and the summaries were prepared under its direction.     

Comparison of salbutamol given intravenously and by intermittent positive-pressure breathing in life-threatening asthma.

A double-blind crossover trial was carried out during 22 episodes of life-threatening asthma in 19 patients to compare salbutamol given as a 500 microgram intravenous injection and as a 0 . 5% solution administered by intermittent positive-pressure breathing (IPPB) for three minutes. Relief of pulsus paradoxus was significantly better after IPPB than the intravenous treatment. Both treatments significantly improved the peak expiratory flow rate. Salbutamol given intravenously produced a mean increase in heart rate of over 20 beats/min five minutes after treatment compared with the relief of tachycardia that occurred after administration by IPPB. Four patients had noticeable cardiovascular side effects after salbutamol given intravenously, but no such effects were noticed after administration by IPPB. Two patients withdrawn shortly after entry into the trial because of a worsening clinical condition had received intravenous salbutamol. It is concluded that salbutamol given by IPPB is better than that given by slow intravenous injection in severe acute asthma.     

Effects of oral and inhaled salbutamol and oral pirbuterol on right and left ventricular function in chronic bronchitis.

In many patients with chronic bronchitis and emphysema right and left ventricular ejection fractions (RVEF and LVEF) are reduced. A study was conducted using multiple gated equilibrium radionuclide ventriculography to compare the effects of oral salbutamol 4 mg and pirbuterol 15 mg on cardiac function in 12 patients with chronic bronchitis (forced expiratory volume in one second 0.86 (SEM 0.12) 1; arterial oxygen pressure 8.2 (SEM 0.5) kPa (61.7 (SEM 3.8) mm Hg)). Different doses of nebulised salbutamol (500 microgram and 5 mg) were also compared in nine of the patients. Both oral salbutamol and oral pirbuterol produced significant increases in RVEF and LVEF at 60 and 90 minutes after drug ingestion (p less than 0.01 in each case). There were no significant differences between salbutamol and pirbuterol in their effects on RVEF and LVEF. Inhaled salbutamol at doses commonly prescribed had no significant effect on RVEF and LVEF after 20 and 60 minutes. Salbutamol and pirbuterol given by mouth have similar actions on RVEF and LVEF. Further studies are necessary to assess the effects of long term B2 agonists in this group of patients.     

Beclomethasone dipropionate dry-powder inhalation compared with conventional aerosol in chronic asthma.

In a double-blind study beclomethasone dipropionate inhaled as a dry powder in doses of 100 microgram four times daily and 150 microgram four times daily was compared with the conventional aerosol dose of 100 microgram four times daily in 20 outpatients with chronic asthma. Each of the three treatments was given for four weeks. The dry powder in a dose of 150 microgram four times daily had advantages over the other two treatments in terms of FEV1 and the number of exacerbations of asthma during the study. There were no adverse reactions to inhaling dry-powder beclomethasone. It was concluded that this new way of administering the drug was effective in chronic asthma, and should allow most patients with chronic asthma who cannot use conventional pressurised aerosols efficiently to benefit from inhaled corticosteroid treatment.     

Emphysema in chronic bronchitis and asthma; a practical therapeutic approach

Asthma and chronic bronchitis are characterized by bronchial occlusion in expiration. Acute spasmodic asthma, if prolonged, may bring about changes in thoracic structure and diaphragm position which can result in permanent pulmonary inefficiency unless this tendency is corrected by breathing exercises. As expiratory obstruction becomes more chronic, irreversible emphysema develops. Thereafter therapy for bronchopulmonary insufficiency is necessary. The approaches to such therapy have been outlined and briefly evaluated, with emphasis upon the value of intermittent positive-pressure therapy.     

Intravenous treatment with rimiterol and salbutamol in asthma.

The bronchodilating efficacies and beta2-adrenoceptor selectivities of rimiterol (0.2, 0.1, and 0.05 mug kg-minus1 min-minus1) and sal-utamol (0.1, 0.5, and 0.025 mug kg-minus1 min-minus1), intravenously infused for one hour, were determined in five patients with chronic asthma. Each drug infusion produced and maintained a dose-related improvement in forced expiratory volune in one second (FEV1). A further increase in FEV1 was produced by inhalation of the same drug by pressurized aerosol at the end of each infusion, which suggested that no resistance had occurred. Similar dose-related increases in heart rate, pulse pressure, and skeletal muscular tremor were produced by each drug. Peak heart rate increases varied greatly between individuals, ranging from 12 to 30 beats/min with the high doses but always less than 10 beats/min with the low doses of each drug. On rimiterol the heart rate reached equilibrium earlier during the infusions and declined more rapidly after they had stopped, thus providing an accurate means for monitoring dosage. Rimeterol with its short half life-a desirable property for an intravenous drug with respect to safety-may prove to be a valuable bronchodilator in severe asthma when intravenous infusions are indicated.