Does the mode of inhalation affect the bronchodilator response in patients with severe COPD?

Spacing devices improve lung deposition of aerosols from metered dose inhalers (MDI) but it is sometimes difficult for dyspnoeic patients to perform maximal breaths with breath-holds needed to inhale the aerosols from them. Our aim was to determine whether the response to bronchodilators (BD) depended on the method of inhalation. We studied 20 patients with moderately severe chronic obstructive pulmonary disease (COPD) with a mean age of 68 years and a mean of forced expiratory volume in 1 sec (FEV1) of 41% predicted. In a randomized, cross-over fashion they inhaled terbutaline 1.5 mg (six puffs) followed by ipratropium 120 microg (six puffs) via MDI and nebuhaler with either two inspirations to total lung capacity and a 10-sec breath-hold per puff or with six tidal breaths per puff. Before and after BDs we measured FEV1, forced vital capacity (FVC), airways resistance using interrupter method (Rint) and 6-min walking distance (6MWD). Subsequently, we re-tested nine of these patients with the two methods of inhalation, before and after conventional doses (terbutaline 500 microg+ipratropium 40 microg), then after terbutaline 1 mg and ipratropium 80 microg and finally after nebulized terbutaline 5 mg and ipratropium 500 microg to sec whether there was a dose-dependent difference in effect between the two methods. Spirometry, slow vital capacity (SVC). inspiratory capacity and shuttle walking tests were monitored. In the original 20 patients there were highly significant improvements in all parameters after inhalers, with no significant difference between methods of inhalation. Median improvements after BDs were: FEV1 0.221 and 0.191, FVC 0.501 and 0.381 and 6MWD 40 m and 44 m, for maximal breaths and tidal breathing, respectively. For nine patients, tidal and maximal breaths produced similar effects on lung function and exercise tolerance at both doses of BDs. Nebulized BDs only improved shuttle distances slightly when compared with either method of inhalation from MDI and spacer but had no additional effect on lung function. In conclusion, in patients with moderately severe COPD, BDs given by metered dose inhaler via nebuhaler have similar effects whether given by six easy tidal breaths or the more difficult two maximal breaths with breath-hold. This holds true at small or larger doses of BD. Either method of inhaling six puffs of the BDs can be used as an effective alternative to nebulized aerosol.

Randomised placebo-controlled crossover trial on effect of inactivated influenza vaccine on pulmonary function in asthma.

BACKGROUND: Despite current recommendations, many people with asthma do not receive annual vaccination against influenza, partly because of concern that vaccine may trigger exacerbations. Colds can trigger exacerbations, which may be mistaken for vaccine-related adverse events. We undertook a double-blind placebo-controlled multicentre crossover study to assess the safety of influenza vaccine in patients with asthma, with allowance for the occurrence of colds. METHODS: We studied 262 patients, aged 18-75 years, who recorded daily peak expiratory flow (PEF), respiratory symptoms, medication, medical consultations, and hospital admissions for 2 weeks before the first injection and until 2 weeks after the second injection. Order of injection (vaccine and placebo) was assigned randomly. There was an interval of 2 weeks between injections. The main outcome measure was an exacerbation of asthma within 72 h of injection (defined as a fall in PEF of >20%). FINDINGS: Among 255 participants with paired data, 11 recorded a fall in PEF of more than 20% after vaccine compared with three after placebo (McNemar's test p=0.06); a fall of more than 30% was recorded by eight after vaccine compared with none after placebo (binomial test p=0.008). However, when participants with colds were excluded, there was no significant difference in the numbers with falls of more than 20% between vaccine and placebo (six vs three; binomial test p=0.51), although the difference for PEF decreases of more than 30% approached significance (five vs none; binomial test, p=0.06). This association was confined to first-time vaccinees. INTERPRETATION: Our findings indicate that pulmonary-function abnormalities may occur as a complication of influenza vaccination. However, the risk of pulmonary complications is very small and outweighed by the benefits of vaccination.

Evaluation of active anterior and posterior rhinomanometry in normal subjects.

In this study active anterior (AAR) and active posterior (APR) rhinomanometry were performed by 100 normal subjects with a Mercury rhinomanometer according to the recommendations of the International Standardization Committee. There was no significant difference between total nasal airway resistance (Rna) values obtained with APR by direct measurement and those calculated from AAR. Mean total Rna was 0.31 Pa/cm3/s (range 0.13-0.84) at a reference pressure of 75 Pa. Measurements by AAR were more reproducible than those by APR, mean intrasubject coefficients of variation were 12 and 16% respectively. This reproducibility was similar to that of lower airways' resistance measurements. Rna values from this population did not conform to a normal Gaussian distribution. Rna was higher during expiration than inspiration and values were higher in women than in men.

Comparison of oscillation with three other methods for measuring nasal airways resistance.

In this study we have compared the sensitivity and reproducibility of nasal airways resistance measurements made using an oscillometer, with those made by passive anterior, active anterior and active posterior rhinomanometry. Nasal airways resistance values were compared in 12 patients with rhinitis and 15 normal subjects, of whom ten had additional measurements after a vasoconstrictor spray, oxymetazoline. The coefficients of variation of 6-8 technically satisfactory measurements were 9-19%. The decongestant effect of oxymetazoline was detected by all methods, with no decrease in reproducibility. Post vasoconstrictor nasal airways resistance fell by 28% (passive anterior), 35% (active anterior), 36% (active posterior) and 58% (oscillometry). In conclusion, the oscillation method for deriving nasal airways resistance is a useful, new, simple and noninvasive way of assessing nasal airways patency. Results compare favourably with other, more established techniques.

Effect of dietary supplementation with fish oil lipids on mild asthma.

Recruitment of inflammatory leucocytes to the airways may play a part in the pathogenesis of asthma. As dietary enrichment with fish oil lipids can suppress leucocyte function, the effect of these lipids on asthma control and neutrophil function was studied in 20 subjects with mild asthma. Twelve subjects received capsules containing 3.2 g of eicosapentaenoic acid and 2.2 g of docosahexaenoic acid daily and eight subjects received placebo capsules containing olive oil for 10 weeks in a double blind fashion. Baseline specific airways conductance, airways responsiveness to histamine and exercise, diurnal peak expiratory flow, symptom scores, and bronchodilator use were measured. Neutrophil fatty acid composition was evaluated by gas chromatography, calcium ionophore induced neutrophil leukotriene (LT)B4 and LTB5 generation were measured by reverse phase high performance liquid chromatography and radioimmunoassay, and neutrophil chemotactic responses to formyl-methionyl-leucyl-phenylalanine (FMLP) and LTB4 were assessed by a microchemotaxis technique. Although the fish oil supplemented diet produced a greater than 10 fold increase in the eicosapentaenoic acid content of neutrophil phospholipids, there was no significant change in airways responsiveness to histamine or any change in any of the clinical measurements. After dietary supplementation with fish oil there was a 50% inhibition of total LTB (LTB4 + LTB5) generation by ionophore stimulated neutrophils and neutrophil chemotaxis was substantially suppressed. Neutrophil function remained unchanged in the placebo group. It is concluded that in subjects with mild asthma a fish oil enriched diet attenuates neutrophil function without changing the severity of asthma.

Pulmonary epithelial permeability in bronchiectasis.

We measured pulmonary epithelial permeability in 17 non-smoking patients with generalized bronchiectasis, of whom six had cystic fibrosis, by determining the half-time clearance from lung to blood (T1/2LB) of inhaled 99mTc-labelled diethylene triamine pentaacetate. Their age range was 15-79 years and the range of their FEV1 measurements was 20-87% of the predicted normal. Sputum obtained by prestudy chest physiotherapy revealed significant colonies of Pseudomonas aeruginosa in six, Haemophilus influenzae in three, Staphylococcus aureus in three and Pasteurella mitocida in one patient, while in the remainder there was normal flora only. Lung clearance was significantly faster in the 13 culture-positive patients (mean T1/2LB = 28 minutes) compared with the four culture-negative patients (mean T1/2LB = 54 minutes). There was no correlation between T1/2LB and prestudy FEV1. The study was repeated in six patients following a course of antibiotics. In two patients only was the sputum cleared of organisms and in those the lung permeability decreased significantly. There was no change in lung permeability in the four patients in whom it was impossible to eradicate the sputum organisms. Thus, in our patients with generalized bronchiectasis, lung permeability was increased only in those with both purulent sputum and significant colonization of the respiratory tract by bacterial pathogens. However, this increase in lung permeability was not associated with worse lung function.

Comparison of the effects of histamine H1- and H2-receptor agonists on large and small airways in normal and asthmatic subjects.

It is accepted that histamine H1-receptors are present on human bronchial smooth muscle and that they mediate bronchoconstriction. However, the role of the histamine H2-receptor in the airways of man is less certain. In ten non-asthmatic and five asthmatic subjects we have compared the effects of inhalation of a specific H1-receptor agonist, betahistine, a specific H2-receptor agonist, impromidine and the combined H1- and H2-receptor agonist, histamine, on specific airways conductance and measurements from partial expiratory flow-volume curves. Both histamine and betahistine induced reproducible dose-dependent bronchoconstriction in all subjects, as assessed by all measurements made. Impromidine had no effect on measurements of airways function in either group of subjects. These results confirm the presence of bronchoconstricting H1-receptors, and the absence of significant numbers of H2-receptors on human bronchial smooth muscle. There is no difference in the distribution of these receptors in normal and asthmatic subjects.

Effect of an oral H1-receptor antagonist, terfenadine, on antigen-induced asthma.

We have investigated the effect of a specific H1-receptor antagonist, terfenadine, on antigen-induced asthma. In a double-blind, randomized fashion, nine stable asthmatics were given placebo, or terfenadine 60, 120 or 180 mg orally, 12 and 4 hours before challenge. Cumulative bronchial challenge with specific antigen aerosols were delivered from a nebulizer attached to a breath-actuated dosimeter. Response was monitored by specific airway conductance and measurements from partial expiratory flow-volume curves, performed in a body plethysmograph, on line to a computer. Initially the histamine dose-response curves of four subjects were found to be shifted 10-fold to the right by terfenadine 60 mg, given orally. Compared with placebo, terfenadine 60 mg, given orally. Compared with placebo, terfenadine significantly shifted the mean antigen dose-response curves of all measurements to the right. However, this shift was small and not correlated to the dose of terfenadine. There was marked intersubject variation in the effect. Terfenadine produced no side effects. The immediate bronchial response to antigen can be attenuated by an oral H1-receptor antagonist, but the effect is small and, in general, unlikely to be clinically useful.

Assessment of nasal airway patency: a comparison of four methods.

Two established methods (active posterior and passive anterior rhinomanometry) and 2 new methods (peak nasal inspiratory flow rate and apparent nasal volume) were used in 12 volunteers to assess the patency of the nasal airways under each of 4 conditions (baseline, post-exercise, nasal histamine and nasal cocaine). All methods showed the congestant effect of histamine but the peak nasal inspiratory flow and apparent nasal volume techniques were more sensitive to the 'decongesting' manoeuvres, (exercise and cocaine). Useful objective quantitative data on the patency of the nasal airways and its changes in response to stimuli can be obtained by simple, cheap and readily available techniques. Subjective sensation is a poor guide to the state of patency of the nasal airways.

Effect of H1- and H2-receptor antagonists on sputum volume and lung function in patients with generalized bronchiectasis.

In a placebo-controlled trial, the effect was assessed of an histamine H1-receptor antagonist, terfenadine (60 mg twice daily) and an H2-receptor antagonist cimetidine (400 mg twice daily) on the sputum production, dyspnoea score and lung function of 12 adult patients with generalized bronchiectasis. Three of these patients had cystic fibrosis. Neither drug, whether given alone or in combination, had any demonstrable effect on any of the parameters measured. It is concluded that histamine plays no significant role in the bronchial hypersecretion occurring in bronchiectasis.

Histamine receptors in the bronchi.

There is considerable variability in the effect of histamine between species and between different sites within the airways. This is probably due to differences in the distribution of histamine receptors. In general, H1-receptors, which predominate in the airways of most species, mediate bronchoconstriction and H2-receptors mediate bronchodilation. In man, particularly in asthmatics, histamine is a powerful bronchoconstrictor, due to the predominance of bronchoconstricting H1-receptors in the airways. H1-receptor antagonists, given in adequate dosage, relieve bronchial tone in asthmatics, prevent histamine-induced bronchospasm in normal and asthmatic subjects and partially prevent both antigen- and exercise-induced asthma. The evidence concerning the presence and function of H2-receptors in human airways is contradictory, but, if present, their role is trivial. There is no difference in the pattern of histamine receptors in normal and asthmatic subjects.

Effect of atropine on experimentally-induced airway obstruction in man.

The effect of pretreatment with inhaled atropine methonitrate 1.5 mg and placebo was compared on standardized inhalation challenges with histamine acid phosphate in normal and asthmatic subjects and with antigen in atopic asthmatics. The response was monitored with measurements of specific airway conductance (sGaw). Challenges were repeated, as often as necessary, to obtain responses whose baseline sGaw after premedication varied by less than 35% within an individual. The anticholinergic effect of atropine 1.5 mg was studied on the methacholine response in all subjects. Atropine inhibited the methacholine response and, therefore, the dose was judged adequate to produce cholinergic blockade in the airways. Similar degrees of bronchodilatation (47-49% increase in sGaw) were found in normal subjects and in non-atopic asthmatics, but greater bronchodilatation was achieved in atopic asthmatics (100% increase in sGaw). Among the asthmatics, the lower the initial sGaw the greater the bronchodilatation with atropine. When prechallenge bronchial tone was comparable within individuals, atropine inhibited the mean histamine response of both normal and asthmatic groups and inhibited the mean antigen response of the atopic asthmatics, whereas placebo had no significant effect. No correlation was found between post-atropine sGaw and the effect of atropine on either histamine or antigen response. In conclusion, atropine is a powerful bronchodilator, particularly in atopic asthmatics with increased bronchomotor tone. Histamine- and antigen-induced bronchoconstriction is inhibited by atropine, but the extent of this inhibition varies between subjects.U

The role of histamine receptors in asthma.

1. Eighteen non-asthmatic and 18 asthmatic subjects underwent challenge with increasing doses of histamine from a dosimeter-nebulizer system. Half the subjects in each group were atopic and half non-atopic. Bronchial response was monitored with serial measurements of specific airways conductance (sGaw) and a dose-response curve was constructed for each challenge. In addition, the nine atopic asthmatic patients underwent antigen challenges with a similar technique. In each subject the challenges were repeated, on separate days, after intravenous injections of either sodium chloride solution (150 nmol/l: saline) placebo, chlorpheniramine (an H1-receptor antagonist), cimetidine (an H2-receptor antagonist) or after both antagonists together. Baseline bronchial tone was always comparable within subjects immediately before challenge. 2. Cimetidine had no significant effect on baseline sGaw in any group, whereas chlorpheniramine raised baseline sGaw in the asthmatic subjects. Placebo did not alter the mean dose-response curves for histamine or antigen. However there was a small, but significant, shift of the curves to the right after cimetidine and a much larger shift to the right with chlorpheniramine, whether given alone or with cimetidine. The effect of the histamine antagonists on histamine and antigen responses was very similar and there was no difference in the pattern of response among normal subjects as compared with asthmatics or among atopic as compared with non-atopic subjects. 3. In conclusion, the same pattern of histamine receptors exists in the airways of asthmatic and normal subjects. Histamine-induced bronchoconstriction is mediated predominantly via the H1-receptors, with little, if any, contribution from the H2-receptors. Histamine appears to be an important mediator in the immediate allergic response in airways since this response is blocked by an H1-receptors antagonist.