Effect of acute alterations in inspired oxygen tension on methacholine induced bronchoconstriction in patients with asthma

BACKGROUND: Recent in vitro and in vivo studies in animals have suggested that ambient oxygen tension may influence airway responsiveness to bronchoconstrictor stimuli. These observations may have relevance to the management of acute exacerbations of asthma. The present studies were designed to examine the influence of inspired oxygen tension (Fio2 1.0, 0.21, 0.15) on methacholine-induced broncho- constriction in patients with asthma. METHODS: In a dual study two groups of asthmatic patients performed methacholine inhalation challenges breathing either air (Fio2 0.21) or a hypoxic gas mixture (Fio2 0.15) in study 1 and air (Fio2 0.21) or hyperoxia (Fio2 1.0) in study 2. The gases were administered through a closed breathing circuit in a randomised double blind fashion. The PC20 values (dose of methacholine causing a 20% fall in forced expiratory volume in one second (FEV1) were calculated after each methacholine challenge by linear interpolation from the logarithmic dose response curve. Plasma catecholamine levels were measured before and after methacholine challenges as well as heart rate, oxygen saturation, and percentage end tidal carbon dioxide levels. RESULTS: The geometric mean PC20 value for methacholine was significantly lower on the hypoxic study day than on the normoxic day in study 1 (mean difference in PC20 values 2.88 mg/ml (95% CI 1.4 to 5.3); p < 0.05), but there was no significant difference in the geometric mean PC20 value for methacholine between the hyperoxic and normoxic study days in study 2 (mean difference in PC20 values 1.45 mg/ ml (95% CI 0.83 to 2.51)). CONCLUSIONS: Acute hypoxia potentiates methacholine induced bronchoconstriction and acute hyperoxia has no effect in mild to moderate patients with stable asthma.




     

Abolition of methacholine induced bronchoconstriction by the hyperventilation of exercise or volition.

Total pulmonary resistance was measured from continuous records of flow and oesophageal pressure in five normal subjects on three separate days before and after inhalation of methacholine. The dose of methacholine produced, on average, a fivefold increase in airway resistance. Immediately after methacholine inhalation the subjects underwent a progressive exercise test on a cycle ergometer (day 1) or voluntary hyperventilation (day 2) or remained resting (day 3). On the first day during exercise pulmonary resistance fell rapidly to baseline levels within two to three minutes and remained there for the 10 minute duration of the exercise. On day 2 voluntary reproduction of the same level and pattern of ventilation as during exercise resulted in a similar fall of resistance. On the third day, when the subjects remained at rest, pulmonary resistance remained raised for 10 minutes. It is concluded that the bronchodilator effects of exercise can be explained by the increased ventilation rather than the exercise itself, but with much smaller tidal volumes than have previously been thought necessary to reduce drug induced bronchoconstriction.     

Spectral characteristics of chest wall breath sounds in normal subjects.

BACKGROUND--This study was carried out to establish a reliable bank of information on the spectral characteristics of chest wall breath sounds from healthy men and women, both non-smokers and smokers. METHODS--Chest wall breath sounds from 272 men and 81 women were measured using contact acoustic sensors, amplifiers, and fast Fourier transform (FFT) based spectral analysis software. Inspiratory and expiratory sounds were picked up at three standard locations on the chest wall during breathing at flows of 1-2 l/s and analysed breath by breath in real time. RESULTS--The amplitude spectrum of normal chest wall breath sounds has two linear parts in the log-log plane--low and high frequency segments--that are best characterised by their corresponding regression lines. Four parameters are needed and are sufficient for complete quantitative representation of each of the spectra: the slopes of the two regression lines plus the amplitude and frequency coordinates of their intersection. The range of slopes of the high frequency lines was -12.7 to -15.2 dB/oct during inspiration and -13.4 to -20.3 dB/oct during expiration. The frequency at which this line crossed the zero dB level--that is, the amplitude resolution threshold of the system--was designated as the maximal frequency (Fmax) which varied from 736 to 999 Hz during inspiration and from 426 to 796 Hz during expiration with higher values in women than in men. The mean (SD) regression coefficient of the high frequency line was 0.89 (0.05). CONCLUSIONS--These data define the boundaries of normal chest wall breath sounds and may be used as reference for comparison with abnormal sounds.     

Effect of sleep deprivation on overnight bronchoconstriction in nocturnal asthma.

Nocturnal cough and wheeze are common in asthma. The cause of nocturnal asthma is unknown and there is conflicting evidence on whether sleep is a factor. Twelve adult asthmatic subjects with nocturnal wheeze were studied on two occasions: on one night subjects were allowed to sleep and on the other they were kept awake all night, wakefulness being confirmed by electroencephalogram. Every patient developed bronchoconstriction overnight both on the asleep night, when peak expiratory flow (PEF) fell from a mean (SE) of 418 (40) 1 min-1 at 10 pm to 270 (46) 1 min-1 in the morning, and on the awake night (PEF 10 pm 465 (43), morning 371 (43) 1 min-1). The morning values of PEF were, however, higher (p less than 0.1) after the awake night and both the absolute and the percentage overnight falls in PEF were greater when the patients slept (asleep night 38% (6%), awake night 20% (4%); p less than 0.01). This study suggests that sleep is an important factor in determining overnight bronchoconstriction in patients with nocturnal asthma.     

Decrease of histamine induced bronchoconstriction by caffeine in mild asthma.

BACKGROUND--While high doses of caffeine may affect pulmonary function and bronchial challenge tests in patients with mild asthma, the effects of lower doses (< or = 5 mg/kg) are less well documented. Specific recommendations exist for withholding theophylline, but not caffeine, before bronchoprovocation and pulmonary function testing. METHODS--To assess the effect of a single oral dose of caffeine (5 mg/kg) on FEV1 and bronchial responsiveness to histamine a double blind, placebo controlled study was performed in eight patients with mild stable asthma. RESULTS--While caffeine had no effect on FEV1, mean (95% confidence interval) log PC20 histamine was significantly higher 150 minutes [caffeine = 0.99 (0.2) mg/ml, placebo = 0.53 (0.29)] and 240 minutes [caffeine = 0.89 (0.24), placebo = 0.44 (0.26)] after administration of caffeine than after placebo. CONCLUSIONS--Caffeine should be excluded from the diet for a period of more than four hours before bronchial provocation testing. The exact length of time for which it must be excluded requires further study.     

Airway response to methacholine during exercise induced refractoriness in asthma.

To investigate the mechanisms contributing to refractoriness in exercise induced asthma a methacholine challenge test was performed 30 minutes before and 30 minutes after two exercise tests 45 minutes apart. Exercise was performed by 12 asthmatic patients while they were breathing cold air. There was a smaller airway response to the second exercise test than to the first, though there was wide variation between subjects. The response to the second methacholine challenge was reduced in some patients but showed no significant change overall. Refractoriness to exercise induced asthma positively correlated with a reduced response to methacholine. These data suggest that mediator depletion does not fully explain refractoriness.     

Effect of verapamil and sodium cromoglycate on leukotriene D4 induced bronchoconstriction in patients with asthma.

Leukotriene D4 (LTD4) may be an important mediator in asthma. The effect of verapamil and sodium cromoglycate on LTD4 induced bronchoconstriction has been examined in seven patients with asthma. The bronchoconstrictor response to increasing concentrations of inhaled LTD4 (0.0032-50 micrograms/ml) was assessed by measuring changes in FEV1, specific airways conductance, and flow rate at 30% of vital capacity (V30(p)). Results were expressed as the provocation concentration (PC) producing a 10% fall in FEV1 (PC10FEV1), a 35% fall in specific airways conductance (PC35SGaw), and a 30% fall in flow at 30% of vital capacity (PC30 V30(p)). Neither verapamil nor cromoglycate inhibited LTD4 induced bronchoconstriction in asthmatic subjects. These results suggest that in asthmatic patients LTD4 induced bronchoconstriction is not mediated via verapamil or cromoglycate sensitive mechanisms.     

Effects of calcium channel blockade on histamine induced bronchoconstriction in mild asthma.

Inhalation histamine dose-response curves were constructed 15 minutes after inhalation of saline placebo or verapamil (4 mg) for eight patients with mild atopic asthma in a double blind, random manner. No significant change in baseline specific airways conductance occurred after inhalation of verapamil, though there was a significant decrease in sensitivity to histamine (increase in threshold of response) (p less than 0.01). There was, however, an associated significant increase (p less than 0.01) in the slopes of the subsequent histamine dose-response curves.     

Effect of methacholine induced bronchoconstriction on the pulmonary distribution and plasma pharmacokinetics of inhaled sodium cromoglycate in subjects with normal and hyperreactive airways.

Inhalation treatment may be less effective in the presence of bronchoconstriction because of the reduced penetration of drugs into the airways. The effect of bronchoconstriction on the lung deposition and plasma pharmacokinetics of inhaled sodium cromoglycate was examined. Ten subjects attended the laboratory on three occasions. On the first occasion a bronchial provocation test was performed to determine the concentration of methacholine required to reduce the forced expiratory volume in one second (FEV1) by 20% (PC20). On the two subsequent occasions subjects inhaled either saline or their PC20 methacholine, followed five minutes later by an aerosol containing sodium cromoglycate and stannous phytate labelled with technetium-99m. Twenty minutes later a gamma emission lung scan was performed to determine the intrathoracic deposition of the nebulised aerosol. The central:peripheral (C:P) ratio of lung deposition was then calculated. Measurements of FEV1 were made and blood samples taken for analysis of plasma sodium cromoglycate concentration at intervals for four hours. Methacholine led to a 23.4% (SEM 0.6%) lower FEV1 and a 2.8 times higher C:P ratio than those observed after saline. There was a direct correlation between log PC20 methacholine and the increase in the C:P ratio (r = 0.81). Despite these changes with methacholine, the plasma pharmacokinetics of inhaled sodium cromoglycate were not significantly different after methacholine and after saline, except that the maximum concentration achieved (Cmax) was increased. These observations suggest that the area of cromoglycate deposition and the anatomical site are less important in determining the plasma pharmacokinetics of cromoglycate than is the total dose delivered to the lung.     

Effect of azelastine on bronchoconstriction induced by histamine and leukotriene C4 in patients with extrinsic asthma.

Azelastine, a new oral agent with antiallergic and antihistamine properties, has been shown to inhibit the effect of histamine and leukotriene (LT) in vitro, though not a specific leukotriene receptor antagonist. The effect of both a single dose (8.8 mg) and 14 days' treatment (8.8 mg twice daily) with azelastine on bronchoconstriction induced by LTC4 and histamine has been examined in 10 patients with mild asthma in a placebo controlled, double blind, crossover study. LTC4 and histamine were inhaled in doubling concentrations from a dosimeter and the results expressed as the cumulative dose (PD) producing a 20% fall in FEV1 (PD20FEV1) and 35% fall in specific airways conductance (PD35sGaw). The single dose of azelastine produced a significantly greater FEV1 and sGaw values than placebo at 3 hours, but this bronchodilator effect was not present after 14 days of treatment. Azelastine was an effective H1 antagonist; after a single dose and 14 days' treatment with placebo the geometric mean PD20FEV1 histamine values (mumol) were 0.52 (95% confidence interval 0.14-1.83) and 0.54 (0.12-2.38), compared with 22.9 (11.5-38.3) and 15.2 (6.47-35.6) after azelastine (p less than 0.01 for both). LTC4 was on average 1000 times more potent than histamine in inducing bronchoconstriction. Azelastine did not inhibit the effect of inhaled LTC4; the geometric mean PD20FEV1 LTC4 (nmol) after a single dose and 14 days' treatment was 0.60 and 0.59 with placebo compared with 0.65 and 0.75 with azelastine. The PD35sGaw LTC4 was also unchanged at 0.66 and 0.73 for placebo compared with 0.83 and 0.74 for azelastine. Thus prolonged blockade of H1 receptors did not attenuate the response to LTC4, suggesting that histamine and LTC4 act on bronchial smooth muscle through different receptors. Four patients complained of drowsiness while taking azelastine but only one who was taking placebo and three patients complained of a bitter, metallic taste while taking azelastine.     

Effect of GR32191, a potent thromboxane receptor antagonist, on exercise induced bronchoconstriction in asthma.

Previous work suggests a role for mast cell derived mediators in exercise induced asthma. The contribution of newly generated contractile prostaglandins to exercise induced asthma was assessed by using a potent and orally active thromboxane (TP1) receptor antagonist, GR32191. The effect of 120 mg GR32191 on exercise induced asthma was observed in 12 asthmatic subjects. For the exercise challenge the subjects performed six minutes of treadmill exercise, breathing dry air at a work load that had previously been shown to induce a fall in FEV1 of 25% or more from the pre-exercise baseline. No effect of GR32191 on pre-exercise baseline airway calibre was evident. There was no significant difference in the mean maximum percentage fall in FEV1 from baseline after exercise between drug and placebo (placebo 30.2%, GR32191 day 31.6%). It is concluded that the thromboxane antagonist GR32191 has no effect on exercise induced asthma. This suggests that prostaglandins, including PGD2, that act via the thromboxane receptor do not have an important role in exercise induced asthma.     

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.     

Effect of nifedipine on arterial hypoxaemia occurring after methacholine challenge in asthma.

To investigate whether the effects of nifedipine on methacholine induced broncho-constriction could impair pulmonary gas exchange in bronchial asthma a randomised, double blind, crossover study in 13 symptom free asthmatic subjects was designed. Each patient underwent a methacholine bronchial challenge test on two separate days one week apart, after having either oral nifedipine (20 mg thrice daily) or placebo for three days. Arterial blood gases were measured before and after methacholine challenge in nine subjects. Prechallenge values of forced expiratory volume in one second (FEV1) and arterial oxygen tension (Pao2) were similar after nifedipine and after placebo. After challenge, the cumulative doses of methacholine required to produce a 20% fall in FEV1 (PD20 FEV1) were significantly larger after nifedipine (280 (SD 347)) cumulative breath units (CBU) than after placebo (120 (183) CBU; p less than 0.01). After challenge the fall in Pao2 values (17.1 (1.6) mm Hg; (2.28 (0.21) kPa)) was significantly greater than after placebo (11.7 (2.4) mm Hg; (1.56 (0.32) kPa) p less than 0.03). Our data show that although oral nifedipine significantly reduces airway reactivity in patients with mild bronchial asthma, it also adversely affects pulmonary gas exchange, resulting in a lowered postchallenge Pao2, probably because of worsening ventilation-perfusion relationships.     

Effect of salbutamol on histamine induced bronchoconstriction in healthy infants.

BACKGROUND--The effect of inhaled beta 2 adrenergic drugs on infants with wheezing disorders remains controversial. Salbutamol inhibits the bronchial responsiveness of infants to histamine and nebulised water but whether or not it acts as a bronchodilator in this age group is unclear. The aim of the present study was to determine whether salbutamol can hasten the reversal of histamine induced bronchoconstriction in infants. METHODS--Bronchial challenge with histamine was performed in 40 infants aged 12 months or less with no previous history of respiratory symptoms. Response to histamine was assessed by forced partial expiratory flow/volume curves to measure maximal flow at functional residual capacity (VmaxFRC). After a fall of 40% or more from baseline VmaxFRC, each infant was randomly assigned to receive either salbutamol 0.5% or saline 0.9% solution by nebuliser. The rate of recovery of VmaxFRC and the time to reach baseline VmaxFRC were derived by linear regression. RESULTS--Infants who received salbutamol had a significantly faster rate of recovery (geometric mean 8.5 ml/s/min) than those who received saline (4.1 ml/s/min). Considerable interindividual variation was observed in the time from maximum bronchoconstriction to recovery of baseline VmaxFRC in both groups of subjects. CONCLUSIONS--Salbutamol significantly speeds the reversal of histamine induced bronchoconstriction in infants during the first 12 months of life. This observation provides further evidence to support the presence of functional beta adrenergic receptors in the airways of infants.     

Effect of nedocromil sodium on sulphur dioxide induced bronchoconstriction.

Nedocromil sodium is a pyranoquinoline derivative that has been developed for the treatment of asthma. We report the results of a double blind randomised study of the effect of two doses of nedocromil sodium (2 and 4 mg) and matched placebo, delivered by metered dose pressurised aerosol, on bronchoconstriction induced by sulphur dioxide in six asthmatic subjects. Nedocromil sodium had no effect on baseline lung function. The magnitude of sulphur dioxide induced bronchoconstriction monitored by partial forced expiratory flow at 30% of reference vital capacity was significantly inhibited by nedocromil sodium 4 mg (p less than 0.05) but not by 2 mg. The maximum changes after placebo and after nedocromil 2 mg and 4 mg were -44.7, -32.7, and -11.8 l min-1. The area under the curve monitoring the effect over 6 minutes was significantly inhibited by both doses to the same extent, the mean changes after placebo and after nedocromil 2 mg and 4 mg being -349.3, -31.2, and 44.6 l. Dyspnoea was monitored by visual analogue scale and showed a significant reduction over 6 minutes with both doses of nedocromil. After placebo and after nedocromil 2 mg and 4 mg the mean maximum changes were 31.5, 13.7, and 15.7 mm, and the mean changes in area under the visual analogue scale-time curve were 289, 194, and 151 mm.min respectively.     

Effect of terbutaline on bronchoconstriction induced by nebulised pentamidine.

The severity, duration, and reversibility of pentamidine induced bronchial narrowing was studied with and without pretreatment with nebulised terbutaline 10 mg in an open study of 40 patients seropositive for the human immunodeficiency virus (HIV). All subjects received pentamidine 300 mg in 5 ml water via an Acorn System 22 jet nebuliser. The forced expiratory volume in one second (FEV1) fell in all 20 patients given pentamidine alone, the mean maximum fall being 20.6%. In the 20 patients given pentamidine preceded by nebulised terbutaline the mean maximum fall in FEV1 was 4%; three subjects had a fall in FEV1 of more than 10%.     

Changes in methacholine induced bronchoconstriction with the long acting beta 2 agonist salmeterol in mild to moderate asthmatic patients.

BACKGROUND--Beta-2 agonists protect against non-specific bronchoconstricting agents such as methacholine, but it has been suggested that the protection afforded by long acting beta 2 agonists wanes rapidly with regular treatment. METHODS--The changes in airway responsiveness were investigated during and after eight weeks of regular treatment with salmeterol 50 micrograms twice daily in 26 adult asthmatic patients, 19 of whom were receiving maintenance inhaled corticosteroids. The study was of a randomised, placebo controlled, double blind design. Airway responsiveness to methacholine was measured as PD20 by a standardised dosimeter technique 12 hours after the first dose, at four weeks and eight weeks during treatment (12 hours after the last dose of test medication), and at 60 hours, one week and two weeks after stopping treatment. RESULTS--There were no significant differences between the baseline characteristics of the two groups. A significant improvement in PD20 was seen at all points during treatment with salmeterol compared with the placebo group, with no significant fall off with time. PD20 measurements returned to baseline values after cessation of treatment with no significant difference from the placebo group. CONCLUSIONS--Salmeterol gave significant protection against methacholine induced bronchoconstriction 12 hours after administration. This protection was of small magnitude, but there was no significant attenuation with eight weeks of regular use and no rebound increase in airway responsiveness on stopping treatment in a group of moderate asthmatic patients, the majority of whom were receiving inhaled corticosteroids.     

Role of cysteinyl leukotrienes in adenosine 5'-monophosphate induced bronchoconstriction in asthma

BACKGROUND: Adenosine induced bronchoconstriction in patients with asthma is thought to be mediated by the synthesis and release of autacoids from airway mast cells. In vitro, adenosine induced constriction of asthmatic bronchi is blocked by a combination of specific histamine and cysteinyl leukotriene receptor antagonists, but the relative contribution of these mediators in vivo is unclear. We hypothesised that adenosine induced bronchoconstriction in asthmatic patients may be blocked by pretreatment with the orally active selective cysteinyl leukotriene-1 (CysLT(1)) receptor antagonist, montelukast. METHODS: In a randomised, double blind, crossover study, oral montelukast (10 mg) or placebo was administered once daily on two consecutive days to 18 patients with mild to moderate persistent atopic asthma. Incremental doses of adenosine 5'-monophosphate (AMP) from 0.39 to 400 mg/ml were inhaled by dosimeter and the dose producing a 20% fall in FEV(1) (PC(20)AMP) after AMP inhalation was recorded. Leukotriene E(4) (LTE(4)) urinary concentrations were measured by enzyme immunoassay 4 hours after AMP challenge. RESULTS: Montelukast pretreatment provided highly significant protection against adenosine induced bronchoconstriction, with geometric mean PC(20)AMP values of 52.6 mg/ml (95% CI 35.2 to 78.7) after placebo and 123.9 mg/ml (95% CI 83.0 to 185.0) after montelukast (p=0.006). The geometric mean of the montelukast/placebo PC(20)AMP ratio was 2.4 (95% CI 1.3 to 4.2). Montelukast had no significant effect on 4 hour urinary excretion of LTE(4) compared with placebo. CONCLUSIONS: Selective CysLT(1) receptor antagonism with montelukast provides highly significant protection against AMP induced bronchoconstriction in patients with atopic asthma, implying that cysteinyl leukotrienes are generated from airway mast cells through preferential activation of their A(2B) receptors.