Assessment of bronchodilatation after spontaneous recovery from a histamine challenge in asthmatic children.

BACKGROUND: It would be convenient to be able to measure airway responsiveness to histamine and to bronchodilator drugs on the same day, but whether this can be done reliably is unknown. METHODS: The effect of a prior histamine challenge on the bronchodilator response to salbutamol after spontaneous recovery of FEV1 to 95% of the prechallenge level was studied in two groups of asthmatic children. Fourteen children inhaled 400 micrograms salbutamol after spontaneous recovery from a histamine challenge, followed by a further 100 micrograms salbutamol 20 minutes later. In a second group of eight asthmatic children the study was repeated with 800 micrograms salbutamol, followed by a further 200 micrograms 20 minutes later. RESULTS: After histamine challenge FEV1 returned to baseline in 70 minutes or less on all occasions. The FEV1 20 minutes after 400 micrograms salbutamol was significantly lower after the histamine challenge than on the control day. After the further 100 micrograms salbutamol FEV1 values were similar after the histamine challenge and on the control day. FEV1 values after 800 micrograms salbutamol and the further 200 micrograms dose were not influenced by a prior histamine challenge. CONCLUSIONS: In children with stable asthma in whom FEV1 has returned to baseline after a histamine challenge the FEV1 achieved after 800 micrograms salbutamol is not affected by the histamine challenge. Histamine and bronchodilator responsiveness can thus be assessed reliably on the same day in patients with stable asthma. This has clear advantages for patient care.     

Failure of ipratropium bromide to modify the diurnal variation of asthma in asthmatic children.

Thirty one children with asthma were given 40 micrograms of ipratropium bromide and identical placebo by inhalation three times a day in a double blind, randomised crossover study to test the ability of an anticholinergic drug to modify the diurnal variation in airway calibre and bronchial reactivity. Subjects measured peak expiratory flow rate approximately eight hourly, before and after inhaled salbutamol, for four week periods. Paired t tests and cosinor analysis were used to assess the diurnal variation in airway calibre from the peak expiratory flow rate recorded before salbutamol and to assess the diurnal variation in bronchodilator responsiveness from the increase in peak expiratory flow rate after salbutamol. Maintenance treatment with ipratropium bromide 40 micrograms three times daily reduced the provocative dose of histamine which caused a 20% fall in FEV1 (geometric mean PD20 = 0.78 v 0.49 mg/ml, p less than 0.05), despite an eight to 12 hour gap between the last dose of ipratropium and histamine challenge. It did not, however, diminish the diurnal variation in airway calibre (mean amplitude = 12.7 v 10.1) or in bronchodilator responsiveness (mean amplitude = 62.4 v 63.5). There was no improvement in the clinical state of subjects while they were taking ipratropium bromide.     

Effects of swimming training on aerobic capacity and exercise induced bronchoconstriction in children with bronchial asthma

BACKGROUND: A study was undertaken to determine whether swimming training improved aerobic capacity, exercise induced bronchoconstriction (EIB), and bronchial responsiveness to inhaled histamine in children with asthma. METHODS: Eight children with mild or moderate asthma participated in swimming training every day for six weeks. The intensity of training was individually determined and set at 125% of the child's lactate threshold (LT), measured using a swimming ergometer. Another group of eight asthmatic children served as control subjects. Aerobic capacity and the degree of EIB were assessed by both cycle ergometer and swimming ergometer before and after swimming training. RESULTS: The mean (SD) aerobic capacity at LT increased by 0.26 (0.11) kp after training when assessed with the swimming ergometer and by 10.6 (4.5) W when assessed with the cycle ergometer, and these changes were significantly different from the control group. The mean (SD) maximum % fall in forced expiratory volume in one second (FEV1) to an exercise challenge (cycle ergometer) set at 175% of LT decreased from 38.7 (15.4)% before training to 17.9 (17.6)% after training, but with no significant difference from the control group. There was, however, no difference in histamine responsiveness when compared before and after the training period. CONCLUSION: A six week swimming training programme has a beneficial effect on aerobic capacity but not on histamine responsiveness in children with asthma.     

Relation of the perception of airway obstruction to the severity of asthma

BACKGROUND: Patients with a poor perception of their symptoms of asthma seem to have an increased risk of an asthma attack. The influence of factors such as airway calibre, bronchial hyperresponsiveness, age and sex on the "perceptiveness" of a patient are poorly understood. It is of clinical importance to identify patients who are likely to have a poor perception of their symptoms. We have studied the perception of bronchoconstriction by asthmatic patients during a histamine provocation test and analysed the influence of bronchial obstruction, hyperresponsiveness, sex, and age. We were particularly interested to establish whether there was any difference in perception between subjects with a greater or lesser severity of asthma (expressed as bronchial obstruction, hyperresponsiveness). METHODS: One hundred and thirty four patients with allergic asthma underwent a histamine provocation test. The FEV1 was measured after each inhalation of histamine. Subjects were asked to rate subjective quantification of the sensation of breathlessness on a visual analogue scale (VAS). The relationship between changes in VAS values and the reduction in FEV1 as a percentage of the baseline value was analysed by determining the linear regression slope (alpha) between the two parameters and indicates the perception of airway obstruction. Multiple regression analysis was performed to investigate the effect of baseline FEV1, bronchial hyperresponsiveness, sex and age on the "perceptiveness" for bronchoconstriction. RESULTS: The median value of the slope alpha (indicating the perception of airway obstruction) was 0.91 (25-75th percentile: 0.48-1.45). Age and sex had no influence on the perception of bronchoconstriction. Both initial bronchial tone (baseline FEV1) and bronchial hyperresponsiveness (PC20) showed a significant correlation with the perception of bronchoconstriction. The regression coefficients for FEV1 and 2log PC20 in the multiple regression model were 0.20 and 0.10. Patients who had a low baseline FEV1 and/or a high bronchial responsiveness to histamine were more likely to show a low perceptiveness for bronchoconstriction during the challenge test. CONCLUSIONS: Low baseline FEV1 and high bronchial responsiveness are associated with a low degree of "perceptiveness" for bronchoconstriction. This suggests that patients with a more severe degree of asthma either show adaptation of "perceptiveness" for airway obstruction or that low perceptiveness leads to more severe asthma.     

Changes in neurokinin A (NKA) airway responsiveness with inhaled frusemide in asthma

BACKGROUND: Inhaled frusemide exerts a protective effect against bronchoconstriction induced by several indirect stimuli in asthma which could be due to interference of airway nerves. A randomised, double blind, placebo controlled study was performed to investigate the effect of the potent loop diuretic, frusemide, administered by inhalation on the bronchoconstrictor response to neurokinin A (NKA) and histamine in 11 asthmatic subjects. METHODS: Subjects attended the laboratory on four separate occasions to receive nebulised frusemide (40 mg) or matched placebo 10 minutes prior to bronchial challenge with NKA and histamine in a randomised, double blind order. Changes in airway calibre were followed as forced expiratory volume in one second (FEV1) and responsiveness to the agonists was expressed as the provocative concentration causing a 20% fall in FEV1 from baseline (PC20). RESULTS: Compared with placebo, inhaled frusemide reduced the airway responsiveness to NKA in all the subjects studied, the geometric mean (range) values for PC20NKA increasing significantly (p < 0.001) from 130.3 (35.8-378.8) to 419.9 (126.5-1000) micrograms/ml after placebo and frusemide, respectively. Moreover, a small but significant change in airway responsiveness to histamine was recorded after frusemide, their geometric mean (range) PC20 values being 0.58 (0.12-3.80) and 1.04 (0.28-4.33) mg/ml after placebo and frusemide, respectively. CONCLUSIONS: The decrease in airway responsiveness to NKA after administration of frusemide by inhalation suggests that this drug may interfere with the activation of neurotransmission in human asthma.




     

Cigarette smoke inhalation patterns and bronchial reactivity.

The manner in which a cigarette is smoked varies considerably between individuals and may be an important determinant of the altered bronchial reactivity observed in cigarette smokers. Twenty smokers were examined to determine the relationship between cigarette smoke inhalation patterns and bronchial reactivity. Inhalation patterns were measured non-invasively with a respiratory inductive plethysmograph and these were related to the provocative concentration of histamine that caused a 20% fall in FEV1 (PC20) and to the cough threshold for inhaled citric acid. Histamine PC20 values were inversely correlated with depth and rate of inhalation. Cough threshold was inversely correlated with greater cigarette consumption and with depth of inhalation.     

Relation between the bronchial obstructive response to inhaled lipopolysaccharide and bronchial responsiveness to histamine.

BACKGROUND: Bronchoconstriction has developed after inhalation of lipopolysaccharide in a dose of 20 micrograms in asthmatic patients and of 200 micrograms in normal subjects. This study set out to determine whether the bronchial response to lipopolysaccharide was related to non-specific bronchial responsiveness and atopy. METHODS: Sixteen subjects with a fall in specific airway conductance of 40% (PD40sGaw) after inhaling up to 900 micrograms histamine inhaled 20 micrograms lipopolysaccharide (from Escherichia coli type 026:B6) a week after bronchial challenge with a control solution of saline. The bronchial response over five hours was measured as change in FEV1 and area under the FEV1-time curve. RESULTS: FEV1 fell significantly more after lipopolysaccharide than after diluent inhalation, the difference in mean (SE) FEV1 being 4.6% (5.4%); response was maximal 60 minutes after lipopolysaccharide inhalation and lasted more than five hours. Histamine PD20FEV1 and PD40sGaw correlated with the fall in FEV1 after lipopolysaccharide inhalation. There was no difference in the proportions of responders and non-responders to lipopolysaccharide who were atopic. CONCLUSION: Lipopolysaccharide induced bronchial obstruction is associated with non-specific responsiveness but not with atopy.     

Propranolol inhalation challenge in relation to histamine response in children with asthma.

The relation between airway responsiveness to propranolol and histamine was studied in 32 asthmatic children. Propranolol and histamine were given by nebuliser to a maximum dose of 16 mg/ml and 32 mg/ml respectively and the response was measured as the provocative concentration of agonist causing a 20% fall in FEV1 (PC20). A PC20 histamine value of less than 32 mg/ml was obtained in 24 of the 32 children, of whom 15 had a measurable PC20 propranolol (less than 16 mg/ml). In these 24 children the geometric mean PC20 histamine was 4.5 mg/ml and 14.4 mg/ml respectively in those with and without a measurable PC20 propranolol (p = 0.023). There was a linear relationship between histamine and propranolol PC20 values (r = 0.60), and between PC20 histamine and FEV1 % predicted (r = 0.43), but not between PC20 propranolol and FEV1 % predicted (r = 0.38). In an open time course study in 12 children with asthma recovery of FEV1 after inhaled propranolol was incomplete in seven of the children after 90 minutes. When inhaled propranolol was followed by inhaled ipratropium bromide in a further 11 children FEV1 had returned to baseline in all children after 60 minutes. Thus propranolol inhalation can be used in children with asthma to assess the contribution of the beta adrenergic system to the regulation of bronchial smooth muscle tone. The test has several disadvantages in comparison with histamine provocation-long duration, the prolonged action of propranolol, and the fact that only the children with substantial hyperreactivity to histamine react to propranolol.     

Combined Intravenous Lidocaine and Inhaled Salbutamol Protect against Bronchial Hyperreactivity More Effectively than Lidocaine or Salbutamol Alone

Background: Airway instrumentation in persons with asthma is linked to the risk of life-threatening bronchospasm. To attenuate the response to airway irritation, intravenous lidocaine is recommended (based on animal experiments) and mitigates the response to histamine inhalation in asthmatic volunteers. However, the effects of lidocaine have not been compared with standard prophylaxis with [Greek small letter beta]-sympathomimetic aerosols. Therefore, the effect of lidocaine, salbutamol, combined treatment, and placebo control were tested in awake volunteers with bronchial hyperreactivity.

Methods: After approval from the local ethics committee, 15 persons, who were selected because they showed a decrease in forced expiratory volume in 1 s (FEV1) more than 20% of baseline in response to inhaled histamine in a concentration less than 18 mg/ml (PC20), were enrolled in a placebo-controlled, double-blind, and randomized study. The challenge was repeated on four different days and the volunteers were pretreated with either intravenous lidocaine, inhalation of salbutamol, inhalation of salbutamol plus intravenous lidocaine, or placebo. Lidocaine plasma concentrations were also measured. Statistical analyses included the Friedman test and Wilcoxon's rank sum.

Results: The baseline PC20 was 6.4 +/- 4.3 mg/ml. Intravenous lidocaine and salbutamol aerosol both significantly increased the histamine threshold to 14.2 +/- 9.5 mg/ml and 16.8 +/- 10.9 mg/ml, respectively (mean +/- SD). However, the combination of lidocaine and salbutamol significantly increased the PC20 even further to 30.7 +/- 15.7 mg/ml than did salbutamol or lidocaine alone.     

Citric acid cough threshold and airway responsiveness in asthmatic patients and smokers with chronic airflow obstruction.

The relation between citric acid cough threshold and airway hyperresponsiveness was investigated in 11 non-smoking patients with allergic asthma (mean FEV1 94% predicted) and 25 non-atopic smokers with chronic airflow obstruction (mean FEV1 65% predicted). Cough threshold was determined on two occasions by administering doubling concentrations of citric acid. Seven of the 11 asthmatic subjects and 14 of 25 smokers with chronic airflow obstruction had a positive cough threshold on both test days. Cough threshold measurements were reproducible in both groups (standard deviation of duplicate measurements 1.2 doubling concentrations in asthma, 1.1 doubling concentrations in chronic airflow obstruction). Citric acid provocation did not cause bronchial obstruction in most patients, though four patients had a fall in FEV1 of more than 20% for a short time on one occasion only. No significant difference in cough threshold was found between the two patient groups despite differences in baseline FEV1 values. There was no significant correlation between cough threshold and the provocative concentration of histamine causing a 20% fall in FEV1 (PC20) histamine in either group. Thus sensory nerves can be activated with a tussive agent in patients with asthma and chronic airflow obstruction without causing bronchial smooth muscle contraction.     

Effect of oral terfenadine on the bronchoconstrictor response to inhaled histamine and adenosine 5'-monophosphate in non-atopic asthma.

Inhaled adenosine 5'-monophosphate (AMP) causes bronchoconstriction in atopic asthma, probably after in vivo conversion to adenosine. It has been suggested that adenosine potentiates preformed mediator release from mast cells on the mucosal surface of the airways by interacting with specific purinoceptors, without affecting the release of newly generated mediators. The airway response of nine non-atopic subjects with "intrinsic" asthma to inhaled AMP and the influence of the oral, selective H1 histamine receptor antagonist terfenadine on this response was investigated. The geometric mean provocation concentrations of histamine and AMP required to produce a 20% fall in FEV1 (PC20) were 1.82 and 13 mmol/l. In subsequent placebo controlled time course studies the FEV1 response to a single inhalation of the PC20 histamine was ablated after pretreatment with oral terfenadine 180 mg. This dose of terfenadine caused an 80% inhibition of the bronchoconstrictor response to the PC20 AMP when measured as the area under the time course-response curve and compared with the response to PC20 AMP preceded by placebo. Terfenadine 600 mg failed to increase protection against AMP further, but both doses of terfenadine delayed the time at which the mean maximum fall in FEV1 after AMP was achieved. Terfenadine 180 mg had no effect on methacholine induced bronchoconstriction in the same subjects. These data suggest that inhaled AMP may potentiate the release of preformed mediators from preactivated mast cells in the bronchial mucosa of patients with intrinsic asthma.     

Potentiating effect of inhaled acetaldehyde on bronchial responsiveness to methacholine in asthmatic subjects.

BACKGROUND--It has recently been reported that acetaldehyde induces bronchoconstriction indirectly via histamine release. However, no study has been performed to assess whether acetaldehyde worsens bronchial responsiveness in asthmatic subjects so this hypothesis was tested. METHODS--Methacholine provocation was performed on three occasions: (1) after pretreatment with oral placebo and inhaled saline (P-S day), (2) after placebo and inhaled acetaldehyde (P-A day), and (3) after a potent histamine H1 receptor antagonist terfenadine and acetaldehyde (T-A day) in a double blind, randomised, crossover fashion. Nine asthmatic subjects inhaled 0.8 mg/ml acetaldehyde or saline for four minutes. After each inhalation a methacholine provocation test was performed. RESULTS--Methacholine concentrations producing a 20% fall in FEV1 (PC20-MCh) on the P-A day (0.48 mg/ml, 95% CI 0.21 to 1.08) and T-A day (0.41 mg/ml, 95% CI 0.22 to 0.77) were lower than those on the P-S day (0.85 mg/ml, 95% CI 0.47 to 1.54). There was no change in the PC20-MCh between the P-A and T-A days. A correlation was observed between the logarithmic values of PC20-MCh (log PC20-MCh) on the P-S day and the potentiating effect of acetaldehyde on the methacholine responsiveness [(log PC20-MCh on P-A day)-(log PC20-MCh on P-S day)] (rho = 0.82). CONCLUSIONS--Acetaldehyde induces bronchial hyperresponsiveness in patients with asthma by mechanisms other than histamine release.     

Effect of an inhaled neutral endopeptidase inhibitor, phosphoramidon, on baseline airway calibre and bronchial responsiveness to bradykinin in asthma.

BACKGROUND--Bradykinin is a potent vasoactive peptide which has been proposed as an important inflammatory mediator in asthma since it provokes potent bronchoconstriction in asthmatic subjects. Little is known at present about the potential role of lung peptidases in modulating bradykinin-induced airway dysfunction in vivo in man. The change in bronchial reactivity to bradykinin was therefore investigated after treatment with inhaled phosphoramidon, a potent neutral endopeptidase (NEP) inhibitor, in a double blind, placebo controlled, randomised study of 10 asthmatic subjects. METHODS--Subjects attended on six separate occasions at the same time of day during which concentration-response studies with inhaled bradykinin and histamine were carried out, without treatment and after each test drug. Subjects received nebulised phosphoramidon sodium salt (10(-5) M, 3 ml) or matched placebo for 5-7 minutes using an Inspiron Mini-neb nebuliser 5 minutes before the bronchoprovocation test with bradykinin or histamine. Agonists were administered in increasing concentrations as an aerosol generated from a starting volume of 3 ml in a nebuliser driven by compressed air at 8 1/min. Changes in airway calibre were measured as forced expiratory volume in one second (FEV1) and responsiveness as the provocative concentration causing a 20% fall in FEV1 (PC20). RESULTS--Phosphoramidon administration caused a transient fall in FEV1 from baseline, FEV1 values decreasing 6.3% and 5.3% on the bradykinin and histamine study days, respectively. When compared with placebo, phosphoramidon elicited a small enhancement of the airways response to bradykinin, the geometric mean PC20 value (range) decreasing from 0.281 (0.015-5.575) to 0.136 (0.006-2.061) mg/ml. In contrast, NEP blockade failed to alter the airways response to a subsequent inhalation with histamine, the geometric mean (range) PC20 histamine value of 1.65 (0.17-10.52) mg/ml after placebo being no different from that of 1.58 (0.09-15.21) mg/ml obtained after phosphoramidon. CONCLUSIONS--The small increase in bronchial reactivity to bradykinin after phosphoramidon exposure suggests that endogenous airway NEP may play a modulatory role in the airways response to inflammatory peptides in human asthma.     

Effects of corticosteroids on bronchodilator action in chronic obstructive lung disease.

BACKGROUND: Short term treatment with corticosteroids does not usually reduce airflow limitation and airway responsiveness in patients with chronic obstructive lung disease. We investigated whether corticosteroids modulate the effects of inhaled salbutamol and ipratropium bromide. METHODS: Ten non-allergic subjects with stable disease were investigated; eight completed the randomised, double blind, three period cross over study. Treatment regimens consisted of 1.6 mg inhaled budesonide a day for three weeks, 40 mg oral prednisone a day for eight days, and placebo. After each period cumulative doubling doses of salbutamol, ipratropium, a combination of salbutamol and ipratropium, and placebo were administered on separate days until a plateau in FEV1 was reached. A histamine challenge was then performed. RESULTS: At the end of placebo treatment mean FEV1 was 55.5% predicted after inhaled placebo, 67.9% predicted after salbutamol and 64.0% predicted after ipratropium. Compared with the results after the placebo period the FEV1 with salbutamol increased by 0.7% predicted after treatment with budesonide and by 0.7% predicted after treatment with prednisone; the FEV1 with ipratropium increased by 0.7% predicted after budesonide and by 4.8% predicted after prednisone; none of these changes was significant. After placebo treatment the geometric mean PC20 was 0.55 mg/ml after placebo, 1.71 mg/ml after salbutamol and 0.97 mg/ml after ipratropium. Compared with the placebo period the PC20 with salbutamol was increased by 0.86 doubling concentrations after treatment with budesonide, and by 0.67 doubling concentrations after prednisone; the PC20 with ipratropium increased by 0.03 and 0.34 doubling concentrations after budesonide and after prednisone respectively compared with placebo; none of these changes was significant. CONCLUSIONS: In non-allergic subjects with chronic obstructive lung disease short term treatment with high doses of inhaled or oral corticosteroids does not modify the bronchodilator response to salbutamol or ipratropium or the protection provided by either drug against histamine. Salbutamol produces greater protection from histamine induced bronchoconstriction than ipratropium.     

Both local anesthetics and salbutamol pretreatment affect reflex bronchoconstriction in volunteers with asthma undergoing awake fiberoptic intubation

BACKGROUND: Awake tracheal intubation may evoke reflex bronchoconstriction in asthmatics. Whether this effect is altered by the choice of the local anesthetic used or by pretreatment with a beta2-adrenoceptor agonist is unknown. Therefore, we assessed the effect of awake fiberoptic intubation after lidocaine or dyclonine inhalation with or without pretreatment with salbutamol on lung function in asthmatic volunteers. METHODS: Bronchial hyperreactivity was verified by an inhalational histamine challenge. On four different days in a randomized, double blind fashion the volunteers (n = 10) inhaled either dyclonine or lidocaine with or without salbutamol pretreatment. FEV1 was measured at baseline, following salbutamol or saline inhalation, after lidocaine or dyclonine inhalation, while intubated, and after extubation. Lidocaine and dyclonine plasma concentrations were also measured. Statistics: Two-way ANOVA, post hoc tests with Bonferroni correction, results are presented as mean +/- SD. RESULTS: Neither lidocaine nor dyclonine inhalation changed FEV1 significantly from baseline compared with placebo inhalation (4.43 +/- 0.67 l vs. 4.29 +/- 0.72 l, and 4.53 +/- 0.63 l vs. 4.24 +/- 0.80 l, respectively). Salbutamol slightly but significantly increased FEV1 (4.45 +/- 0.76 l vs. 4.71 +/- 0.61 l, P = 0.0034, and 4.48 +/- 0.62 l vs. 4.71 +/- 0.61 l, P = 0.0121, respectively). Following awake intubation FEV1 significantly decreased under lidocaine topical anesthesia (4.29 +/- 0.72 l to 2.86 +/- 0.87 l) but decreased even more under dyclonine anesthesia (4.24 +/- 0.80 l to 2.20 +/- 0.67 l; P < 0.0001). While salbutamol pretreatment significantly attenuated the response to intubation, it did not eliminate the difference between the effects of lidocaine and dyclonine. Only minutes after extubation FEV1 was similar compared with baseline. CONCLUSION: In asthmatics, awake fiberoptic intubation evokes a more than 50% decrease in FEV1 following dyclonine inhalation. Using lidocaine for topical anesthesia the decrease in FEV1 is significantly mitigated (35%) and can be even further attenuated by salbutamol pretreatment. Therefore, combined treatment with lidocaine and salbutamol can be recommended for awake intubation while the use of dyclonine, despite its excellent and longer lasting topical anesthesia, may be contraindicated in patients with bronchial hyperreactivity.     

Histamine induced changes in breathing pattern may precede bronchoconstriction in selected patients with bronchial asthma.

BACKGROUND--In asthmatic patients methacholine or histamine challenge may result in more rapid and shallow breathing. Bronchoconstriction can also be associated with changes in the pattern of breathing. However, few studies, particularly in patients with asthma, have investigated the possibility that changes in the pattern of breathing may precede the onset of bronchoconstriction. METHODS--Eight subjects were selected from 34 consecutive asthmatic patients who had previously exhibited a significant increase in respiratory frequency (Rf) and decrease in tidal volume (VT) accompanying a 20% or greater fall in FEV1 during a histamine bronchial provocation test. These patients also had bronchial hyperresponsiveness (histamine PC20FEV1 0.1-0.25 mg/ml). VT, Rf, and the ratio of VT to Rf were evaluated breath by breath under control conditions and two minutes after inhalation of either saline or each of a series of progressively increasing concentrations of histamine. In each subject the coefficient of variation (CV) for each breathing pattern variable was calculated under control conditions and at each histamine concentration over at least 30-40 breaths. For FEV1, VT and Rf step by step coefficients of variation were averaged and the mean (2SD) CV was considered to represent a threshold value in each patient. RESULTS--Histamine challenge resulted in increased Rf and Rf/VT, and decreased VT and FEV1. In all but one subject change in Rf and Rf/VT beyond the threshold value preceded change in FEV1 beyond the threshold value. The threshold concentrations of histamine for Rf and Rf/VT did not correlate with the threshold value for FEV1. CONCLUSIONS--In selected asthmatic patients a change in breathing pattern occurs prior to a change in FEV1. These results suggest that narrowing of the airways, in terms of decrease in FEV1, does not play a major part in the initial change in the pattern of breathing. This may be caused by direct stimulation of vagal airway receptors.     

Effects of methacholine induced bronchoconstriction and procaterol induced bronchodilation on cough receptor sensitivity to inhaled capsaicin and tartaric acid.

BACKGROUND: The direct effect of bronchoconstriction on cough receptor sensitivity is unknown, and the antitussive effect of beta 2 adrenergic agonists in man has been controversial. This study was designed to throw light on these questions. METHODS: The threshold of the cough response to inhaled capsaicin, a stimulant acting on C fibre endings, and tartaric acid, a chemostimulant, was measured before and 10 minutes after inhalation of methacholine, which caused a nearly 20% fall in forced expiratory volume in one second (FEV1), in 14 normal subjects (study 1), and also before and 30 minutes after inhalation of procaterol (30 micrograms), placebo, and saline in eight normal subjects (study 2). Progressively increasing concentrations of capsaicin and tartaric acid solutions were inhaled for 15 seconds by mouth tidal breathing at one minute intervals and cough threshold was defined as the lowest concentration of capsaicin and tartaric acid that elicited five or more coughs. RESULTS: In study 1 the geometric mean values of the cough threshold of response to capsaicin and tartaric acid before methacholine callenge, 2.98 (GSE 1.30) micrograms/ml and 46.6 (1.22) mg/ml, were not significantly different from those of the response to methacholine inhalation, 3.45 (1.33) micrograms/ml and 32.9 (1.37) mg/ml. In study 2 the geometric mean value of the cough threshold of response to capsaicin before inhalation of procaterol (4.61 (GSE 1.84) micrograms/ml) was not different from that after inhalation of procaterol (4.61 (GSE 1.84) micrograms/ml), which had significant bronchodilator effects. The cough threshold was not altered by placebo or saline. CONCLUSIONS: These findings suggest that muscarinic receptor stimulation, bronchoconstriction, beta 2 receptor stimulation, or bronchodilation might have no direct effect on the sensitivity of the cough receptors in normal subjects.     

Airway responsiveness to histamine and methacholine: relationship to minimum treatment to control symptoms of asthma.

We have prospectively examined in 51 patients the relationship between the level of airway responsiveness to histamine and methacholine and the minimum medications required to control asthma. First we determined the least medication that was required to control symptoms so that they did not disturb sleep, were not present on waking, and did not require use of inhaled salbutamol (200 microgram) more than four times daily. When baseline FEV1 was greater than 70% of predicted and when there had been no respiratory infection or allergen exposure for six weeks, histamine and methacholine inhalation tests were carried out on separate days to determine the provocation concentration causing a fall in FEV1 of 20% (PC20). There was a close correlation between the PC20 to the two agents. The patients were grouped into 1, those who required no medication; 2, those who required salbutamol (200 microgram) occasionally but not daily; 3, those who required daily salbutamol; and 4, those who required additional beclomethasone dipropionate. The mean PC20 was highest in group 1 and lowest in group 4; there was a significant difference between each group. The results indicate that airway responsiveness to vasoactive amines is either an important determinant of the severity of asthma and the medication requirements or a consequence of the severity of asthma. They raise the possibility that measurement of responsiveness may be useful in some patients with established asthma to substantiate or question medication needs.     

Effect of pH on bronchial response to inhaled histamine.

In order to investigate the effect of pH on bronchial responsiveness to inhaled histamine, 15 subjects with non-specific bronchial hyperreactivity performed two histamine inhalation tests, one with unbuffered, and the other with buffered histamine acid phosphate solutions. The unbuffered histamine solutions were prepared with 0.9% sterile saline and had a pH range from 4.3 to 7.3, while the buffered histamine solutions were prepared with a phosphate buffer and had a pH range of 6.5 to 7.4. The two histamine inhalation tests were similar in all other regards. The geometric mean histamine provocation concentration required to produce a 20% reduction in FEV1 (PC20) was significantly lower for the unbuffered histamine (1.33 mg/ml) than for the buffered histamine (1.67 mg/ml), p less than 0.05. The two PC20s differed by less than one doubling dilution, the range of reproducibility of the test, in 12 of the 15 subjects. The pH effect was only noted when the pH of the histamine solutions was below five (histamine concentrations from one to eight mg/ml). We conclude that the acid pH of higher concentrations of histamine acid phosphate solutions has a slight but significant enhancing effect on the bronchial responsiveness to inhaled histamine.     

Prevalence of bronchial reactivity to inhaled methacholine in New Zealand children.

The prevalence of bronchial hyperreactivity to inhaled methacholine and of a clinical history of symptoms of asthma was determined in a birth cohort of 9 year old New Zealand children. A history of current or previous recurrent wheezing was obtained in 220 of 815 children. Of 800 who had spirometric tests, 27 (3.4%) had resting airflow obstruction (FEV1/FVC less than 75%). Methacholine challenge was undertaken without problem in 766 children, the abbreviated protocol being based on five breaths and four concentrations. A fall in FEV1 of more than 20% was observed in 176 children (23% of challenges, 22% of the full cohort) after inhalation of methacholine in concentrations of up to 25 mg/ml. The prevalence of bronchial reactivity in children with symptoms was related to the frequency of wheezing episodes in the last year, and the degree of reactivity to the interval since the last episode. Sixty four children (8.0%) with no history of wheeze or recurrent dry cough were, however, also responsive to methacholine 25 mg/ml or less, while 35% of children with current or previous wheezing did not respond to any dose of methacholine. Bronchial challenge by methacholine inhalation was not sufficiently sensitive or specific to be useful as a major criterion for the diagnosis of asthma in epidemiological studies. The occurrence of airway reactivity in children without symptoms of asthma, however, raises the possibility that adult onset asthma and the development of airways obstruction in some subjects with chronic bronchitis could have origins in childhood.