Effects of Repeated Deep Inspirations on Recovery from Methacholine-Induced Airway Narrowing in Normal Subjects

Background. A single deep inspiration (DI) is known to be a potent bronchodilator but it is not known if repeated DI can accelerate sustained recovery from bronchoconstriction. Methods. We induced sustained bronchoconstriction using increasing concentrations of nebulized methacholine (Mch) during tidal breathing and assessed airway narrowing by measuring respiratory resistance (Rrs) using forced oscillation in six healthy subjects. On separate days we examined the effects of DI every 3 minutes and of prohibition of DI on recovery of Rrs for 30 minutes after the end of Mch nebulization. Results. Bronchoconstriction (Rrs ～ 150% above baseline) was induced. DI during recovery had a transient bronchodilator effect but no cumulative effect. At 30 minutes after end of nebulization (and 2 minutes after the last DI) Rrs was 87% above baseline compared to 93% above baseline when DI was prohibited. Conclusion. Recovery from induced bronchoconstriction with methacholine was slow (～ 2%/min) and not accelerated by frequent DI.     

Respiratory impedance response to a deep inhalation in children with history of cough or asthma

The aim of this study was to describe the change in respiratory impedance induced by a deep inhalation (DI) in children who developed a positive response to inhalation of methacholine (Mch). Eighteen children aged 4.5-12.5 years, presenting with chronic cough or doctor-diagnosed asthma, were studied at baseline after inhalation of Mch and after inhalation of a bronchodilator. Respiratory resistance (Rrs) and reactance (Xrs) were measured by the forced oscillation technique, varying transrespiratory pressure at 12 Hz around the head. The tidal flow (V') and volume (V) dependence of Rrs before and after the DI was characterized according to the equation Rrs = K1 + K2 x /V'/ + K3 x V. DI induced no significant change at baseline or after inhalation of a bonchodilator. During Mch challenge, Rrs and K1 were significantly lower, and K3 and Xrs significantly less negative after DI than before, during both inspiration and expiration; there was no change in K2.We conclude that DI results in a decrease in Rrs in children with induced bronchoconstriction. The associated changes in Xrs, K1, and K3, and lack of decrease in K2, suggest that dilatation of airways occurs at the bronchial level, with little contribution of the upper airways or of a change in breathing patterns.     

Airway re-narrowing following deep inspiration in asthmatic and nonasthmatic subjects.

After bronchoconstriction, deep inspiration (DI) causes dilatation followed by airway re-narrowing. Re-narrowing may be faster in asthmatic than nonasthmatic subjects. This study investigated the relationship between re-narrowing and the magnitude of both DI-induced dilatation and the volume-dependence of respiratory system resistance (Rrs) during tidal breathing. In 25 asthmatic and 18 nonasthmatic subjects the forced oscillation technique was used to measure Rrs at baseline and after methacholine challenge, during 1 min of tidal breathing, followed by DI to total lung capacity (TLC) and passive return to functional residual capacity (FRC). Dilatation was measured as the decrease in Rrs between end tidal inspiration and TLC, re-narrowing as Rrs at FRC immediately after DI, as per cent Rrs at end-tidal expiration, and volume dependent tidal fluctuation as the difference between mean Rrs at end-expiration and end-inspiration. Asthmatic subjects had greater re-narrowing, less dilatation, and greater tidal fluctuations both at baseline and after challenge. Re-narrowing correlated with baseline tidal fluctuation and inversely with dilatation. Both baseline tidal fluctuation and dilatation were significant independent predictors of re-narrowing. Following deep inspiration-induced dilatation, faster airway re-narrowing in asthmatic than nonasthmatic subjects is associated not only with reduced deep inspiration-induced dilatation but also with some property of the airways that is detectable prior to challenge as an increased volume dependence of resistance.     

Bronchial Plasma Exudation After Adenosine Monophosphate or Methacholine Challenge

Nonspecific hyperresponsiveness to adenosine monophosphate is better related to airway inflammation than methacholine. Adenosine induces mast cells and other cells to release inflammatory mediators that produce bronchoconstriction and perhaps other inflammatory effects, such as plasma exudation, which have not been well studied. We compared the plasma exudation effect, as measured in induced sputum, between adenosine and methacholine challenge in healthy and asthmatic subjects. In a cross-over design, 42 subjects were randomly challenged with adenosine or methacholine. After recovery, induced sputum was collected on 2 separate days, 48 to 72 hours apart. In the control group, an additional challenge with saline was performed. Differential cell counts and albumin and alpha2-macroglobulin levels were determined. The sputum volume obtained was sufficient to measure proteins in only 34 subjects: 10 healthy individuals and 24 mild asthmatics. There was a significant difference between adenosine and methacholine in sputum albumin (mean differences: 68[73.4] μg/L in controls, p = 0.039 and 48.0[162.9] μg/L in asthmatics) and cell counts, but only a tendency in alpha2-macroglobulin. PC20 adenosine was better related to eosinophil counts than methacholine (r = -0.44, p = 0.014). Albumin or alpha2-macroglubulin levels were not significantly correlated with baseline FEV₁, PC20, or eosinophil counts. Adenosine, but not methacholine challenge, produces a mild airway plasma exudation that does not seem to be relevant to bronchoconstriction. However, this could be relevant, to some supernatant measurements after adenosine challenge.     

Methacholine-induced volume dependence of respiratory resistance in preschool children.

Enhanced negative volume dependence of airway resistance is associated with bronchoconstriction in tracheostomized paralysed open-chest animals. Significant upper airways responses may be associated with bronchoconstriction and could thereby alter the pattern of volume dependence in spontaneously breathing subjects. The aim of the study was to test whether volume dependence of respiratory resistance (Rrs) could be demonstrated in preschool children undergoing routine methacholine challenge. The volume dependence of respiratory oscillation resistance at 12 and 20 Hz (Rrs,12 and Rrs,20) was examined in eight 4-5.5-yr-old children showing a positive response to methacholine. Multiple linear regression analysis was also used to account for flow dependence during tidal breathing (Rrs,12 or Rrs,20=K1+K2?V'?+K3V). Rrs,12 and Rrs,20 yielded similar results. Negative volume dependence was present at baseline and significantly enhanced by methacholine (p<0.01). For instance, the mean+/-SD inspiratory K3 at 20 Hz was 4.1+/-1.3 hPa x s x L(-2) at baseline and -15.0+/-4.3 hPa x s x L(-2) after methacholine, in which case it was also larger on expiration than on inspiration (p<0.05), possibly as a result of upper airway responses. A significant increase in the negative volume dependence of respiratory resistance may thus be shown in preschool children in response to methacholine. The volume dependence (K3) during inspiration may be particularly useful in detecting bronchoconstriction, because it is less likely to be affected by upper airway mechanisms than during expiration.     

Changes in the highest frequency of breath sounds without wheezing during methacholine inhalation challenge in children

A breath sound analyser was used to detect bronchoconstriction without wheezing during methacholine inhalation challenge in children. The highest frequency of inspiratory breath sounds increased significantly during bronchoconstriction and decreased after inhalation of a bronchodilator. The highest frequency of inspiratory breaths sounds was correlated with bronchial reactivity. Background and objective: It is difficult for clinicians to identify changes in breath sounds caused by bronchoconstriction when wheezing is not audible. A breath sound analyser can identify changes in the frequency of breath sounds caused by bronchoconstriction. The present study aimed to identify the changes in the frequency of breath sounds during bronchoconstriction and bronchodilatation using a breath sound analyser. Methods: Thirty‐six children (8.2 ± 3.7 years; males : females, 22 : 14) underwent spirometry, methacholine inhalation challenge and breath sound analysis. Methacholine inhalation challenge was performed and baseline respiratory resistance, minimum dose of methacholine (bronchial sensitivity) and speed of bronchoconstriction in response to methacholine (Sm: bronchial reactivity) were calculated. The highest frequency of inspiratory breath sounds (HFI), the highest frequency of expiratory breath sounds (HFE) and the percentage change in HFI and HFE were determined. The HFI and HFE were compared before methacholine inhalation (pre‐HFI and pre‐HFE), when respiratory resistance reached double the baseline value (max HFI and max HFE), and after bronchodilator inhalation (post‐HFI and post‐HFE). Results: Breath sounds increased during methacholine‐induced bronchoconstriction. Max HFI was significantly greater than pre‐HFI (P < 0.001), and decreased to the basal level after bronchodilator inhalation. Post‐HFI was significantly lower than max HFI (P < 0.001). HFI and HFE were also significantly changed (P < 0.001). The percentage change in HFI showed a significant correlation with the speed of bronchoconstriction in response to methacholine (P = 0.007). Conclusions: Methacholine‐induced bronchoconstriction significantly increased HFI, and the increase in HFI was correlated with bronchial reactivity.     

Respiratory and upper airways impedance responses to methacholine inhalation in spontaneously breathing cats.

The upper airways may contribute to the increase in respiratory resistance induced by methacholine (Mch). The aim of this study was to simultaneously assess the Mch response of upper airways and lower respiratory resistances (Rua, Rrs,lo) and reactances (Xua, Xrs,lo), and to test whether the change of total respiratory resistance and reactance after Mch were affected by upper airways mechanisms. Seven cats breathing spontaneously were studied under chloralose, urethane anaesthesia. Forced oscillations were generated at 20 Hz by a loud-speaker connected to the pharyngeal cavity. A pneumotachograph was placed between rostral and caudal extremities of the severed cervical trachea. Pressure drops were measured across the upper airways and across the lower respiratory system. Rua, Xua, Rrs,lo and Xrs,lo were obtained after nebulized normal saline and Mch administered directly through the tracheostomy. The analysis focused on Mch tests showing clear positive upper airways response. Volume and flow dependence of Rrs,lo and Rua were assessed during tidal inspiration using multiple linear regression analysis. After Mch, Rrs,lo increased and became negatively volume dependent, while the increase in Rua was associated with no significant change in volume dependence; Xrs,lo became negative while Xua did not change. The upper airways response to methacholine may thus contribute to the increase in total respiratory resistance but may not account for either its negative volume dependence or the decrease in total resistance. It is surmised that these features more specifically reflect alterations in respiratory mechanics occurring at the level of the intrathoracic airways.     

Induction and Recovery Phases of Methacholine-induced Bronchoconstriction Using FEV1 According to the Degree of Bronchial Hyperresponsiveness

Forty-eight patients suffering from intermittent bronchial asthma underwent methacholine challenge test. Response was stronger in 29 patients and less pronounced in 19. The two groups had the same characteristics except for the cumulative methacholine dose which was lower in severe hyperresponsiveness. The patients were studied both in the phase of induced bronchospasm and in the subsequent phase of spontaneous recovery. Dose-response curves to methacholine were analyzed as FEV1% decline/methacholine dose for the induction phase of bronchoconstriction and as FEV1% increase*methacholine dose/time after PD20FEV1 for the recovery phase. The phase of induced bronchospasm as well as spontaneous recovery had a linear pattern in severe hyperresponsiveness; in patients with moderate response, induced bronchoconstriction had a curvilinear pattern whereas spontaneous recovery had a linear pattern. This latter group had to break down an amount of methacholine that was fivefold greater than the former, therefore the mechanism of local homeostasis recovery may be more efficient in moderate hyperresponsiveness. However, in both groups recovery after the bronchospasm was not complete after 60 min (p < 0.01 versus baseline). Furthermore, recovery was faster in the first 15 min than in the remaining time. In conclusion the behavior of methacholine-induced bronchospasm and its spontaneous recovery in both severe and moderate hyperresponsiveness seem to be different although several and not well-established mechanisms may be responsible for this phenomenon.     

Influence of data filtering on reliability of respiratory impedance and derived parameters in children

Forced oscillation impedance (Zrs) measurements are frequently corrupted by noisy data in children. Our aim was to improve the reliability of respiratory resistance (Rrs) and routine identification of its flow (V') and volume (V) dependence during tidal breathing, according to Rrs = K1 + K2 x /V'/ + K3 x V. Zrs was measured at 12 Hz, using a head generator in 23 children aged 4-13 years undergoing methacholine (Mch) challenge. Rrs, K1, K2, K3, and residual mean square error (RMSD), as well as reproducibility of the parameters, were obtained. Calculations were performed separately in inspiration and expiration on the raw data, and after eliminating values lying outside confidence intervals ranging from 99% (F3SD) to 95% (F2SD) of the mean Zrs. Filtering decreased RMSD and Rrs, F3SD improved reproducibility of Rrs in expiration compared to raw data. F2SD increased K1 and decreased the amplitude of K2 and K3 before and after Mch compared to F3SD. Rrs and K2 were significantly larger and K3 significantly more negative in expiration than in inspiration at all levels of filtering, probably because of the upper airways. F3SD appeared efficient in eliminating aberrant data, while allowing the identification of physiological variations of Rrs.     

Importance of the angiotensin type 1 receptor in angiotensin II-induced bronchoconstriction and bronchial hyperresponsiveness in the guinea pig

Although angiotensin II (Ang II) causes bronchoconstriction and bronchial hyperresponsiveness to methacholine in mildly asthmatic patients, the responsible mechanisms for these reactions are unclear. The authors examined the effect of intravenous infusion of Ang II on airway constriction in guinea pigs. Furthermore, the effects of subthreshold concentrations of Ang II on bronchial responsiveness to methacholine were investigated. Airway opening pressure (Pao), an index of bronchoconstriction, increased dose dependently after intravenous infusion of 3 and 10 nmol/kg Ang II (72.2 and 236.5 increase above the baseline value, respectively). In another set of experiments, animals received a methacholine inhalation challenge under a constant intravenous infusion of a subthreshold dose of Ang II (2 nmol/kg/min). The Ang II infusion elicited bronchial hyperresponsiveness to methacholine. The provocative concentration of methacholine, which produced a 200% increase above the baseline Pao (PC200), decreased from 306.9 to 156.1 micrograms/mL upon Ang II infusion. Pretreatment with TCV-116, a type 1 Ang II (AT1) receptor antagonist, but not PD123319, a type 2 Ang II (AT2) receptor antagonist, dose dependently prevented both the Ang II-induced bronchoconstriction and bronchial hyperresponsiveness to methacholine. The authors conclude that Ang II caused bronchoconstriction and induced bronchial hyperresponsiveness to methacholine via the AT1 receptors and that this effect did not involve the release of other bronchoactive mediators.     

Inhaled verapamil-induced bronchoconstriction in mild asthma

Methacholine challenges were performed in ten subjects with mild asthma at 2 h before and 20 min after placebo or 5, 10, 20, 40, 80, and 160 mg of inhaled verapamil given in a single-blind randomized crossover manner on different days. While verapamil did not have a bronchodilator effect, the 10-mg dose modestly increased the concentration of methacholine required to decrease FEV1 by 20 percent (PC20). The mean (+/- SEM) increase in PC20 from baseline was 2.1 +/- 0.2 times baseline after 10 mg of verapamil, compared to 1.1 +/- 0.1 times baseline after placebo (p less than 0.001). Unexpectedly, bronchoconstriction (greater than 10 percent decrease in FEV1) associated with cough or wheezing was observed in seven of ten subjects at doses of 20 mg or more. This adverse effect was not related to the osmolarity of the nebulized solutions. Thirty minutes before a standardized exercise challenge, 13 subjects inhaled placebo, 10 mg, or the highest dose of verapamil tolerated during the methacholine study (20 to 160 mg) in a double-blind randomized crossover manner. The exercise challenge was aborted in three subjects because of bronchospasm that occurred after administration of the higher dose. The mean (+/- SEM) maximum change in FEV1 after exercise in the ten subjects completing all three regimens of treatment was -17.1 +/- 4.0 percent after placebo, -12.7 +/- 4.3 percent after 10 mg (p less than 0.05), and -6.4 +/- 3.6 percent after the highest dose (p less than 0.05). We conclude that increasing the dose of verapamil above 10 mg did not provide greater benefit but, paradoxically, induced bronchoconstriction in most of the subjects. Because of this potential bronchoconstrictor effect, high doses of oral or intravenous verapamil should be used with caution in asthmatic subjects.     

Nitrogen oxides reduce albuterol-induced bronchodilation in patients with bronchial asthma

BACKGROUND: We have previously found that asthmatics exhibit higher levels of nitrogen oxides (NOs) in exhaled air and in induced sputum than normal controls, and that NOs altered beta(2)-adrenoceptor (beta(2)-AR) function in an experimental animal model. OBJECTIVES: To determine whether NOs influence the bronchodilator activity of albuterol in asthmatic patients. METHODS: We simultaneously measured the levels of NOs in exhaled air and in induced sputum in 20 asthmatic patients. The bronchodilator activity of albuterol was expressed as spontaneous recovery (before methacholine) and recovery from the lowest value in FEV(1) evoked by the methacholine challenge (after methacholine). After the first study, 400 microg of beclomethasone dipropionate (BDP) was administered twice daily for 1 week to all patients, and the above-mentioned protocols were repeated. RESULTS: The recovery of FEV(1) (before methacholine) after albuterol was not significantly correlated with either baseline FEV(1) or PC(20) methacholine. Nor was the recovery of FEV(1) (after methacholine) after albuterol significantly correlated with the maximal fall in FEV(1) after the methacholine challenge and PC(20) methacholine. However, the recovery of FEV(1) after albuterol was inversely correlated with the nitric oxide levels in exhaled air (before methacholine: r = -0.556, p = 0.0151; after methacholine: r = -0.684, p = 0.0028), and the concentration of nitrite and nitrate in induced sputum (before methacholine: r = -0.459, p = 0.0448; after methacholine: r = -0.830, p = 0.0003). After treatment with inhaled BDP for 1 week, there was no significant change in baseline FEV(1). However, there was a significant decrease in the concentration of nitrite and nitrate in induced sputum (p < 0.0001). The changes in nitrite and nitrate levels in induced sputum after 1 week of BDP therapy were significantly correlated with the changes in bronchodilator activity of albuterol before and after BDP therapy (before methacholine: r = 0.704, p = 0.0022; after methacholine: r = 0.727, p = 0.0015). CONCLUSIONS: We demonstrated that NOs in the airways reduced albuterol-induced bronchodilation in asthmatics.     

Ipratropium Bromide: Bronchodilator Action and Effect on Methacholine-Induced Bronchoconstriction

The effects of ipratropium bromide (80 and 200 μ;g) and placebo on the basal bronchial tone and on methacholine-induced bronchoconstriction were investigated in 10 asthmatic patients in a placebo-controlled double-blind manner. Bronchial hyperreactivity to methacholine was confirmed at a pretrial bronchial challenge. The patients were randomly allocated to two groups in which the drug was inhaled from either metered-dose inhalers (MDI) or powder capsules. With the high dosage, the bronchodila-tion resulting from powder capsules was somewhat more pronounced than that achieved with the MDI. Otherwise the bronchodilator effect of ipratropium bromide and the protection afforded by the drug against methacholine-induced bronchoconstriction were similar in the two groups. In five patients the bronchodilator effect was better and in four patients the tolerance to methacholine was greater after the higher ipratropium dosage than after the lower one. In two patients ipratropium bromide had no bronchodilator effect but gave good protection against methacholine-induced bronchoconstriction. It is concluded that some patients benefit from a dosage of ipratropium bromide higher than that usually recommended and that an anticholinergic effect on the bronchi is possible even in the absence of the bronchodilator effect in the basal state.     

Role of superoxide anions in airway hyperresponsiveness induced by cigarette smoke in conscious guinea pigs

To investigate the involvement of superoxide in airway hyperresponsiveness and bronchoconstriction induced by cigarette smoke (CS), we evaluated the effects of superoxide dismutase (SOD), a scavenger of superoxide anion, and apocynin, an inhibitor of superoxide anion-generating NADPH oxidase in phagocytes, on the airway responses induced by CS in conscious guinea pigs. Airway responsiveness was assessed by PC_2OOMch, the concentration required to produce a doubling in the baseline specific airway resistance (sRaw) to an inhaled methacholine aerosol, in nonanesthetized spontaneously breathing animals. Before being exposed to ten puffs of CS, animals inhaled either SOD (5,000 units/ml or 25,000 units/ml) or vehicle. Although SOD did not affect PC_2OOMch, in the air control group, this agent significantly reduced the CS-induced airway hyperresponsiveness. Repeated administration of apocynin (12 mg/kg for 4 days) did not affect PC_2OOMch, after exposure to CS. These data suggest that the superoxide from CS was involved in the airway hyperresponsiveness induced by CS, whereas phagocytic reactive oxygen species were not. The data also suggest a potential therapeutic role for antioxidants in airway hyperresponsiveness. Offprint requests to: Takao Okubo     

Intratracheal administration of phosphodiesterase III inhibitor attenuates bronchoconstriction in cats: A preliminary report

The effects of intratracheal administration of MKS 492, selective phosphodiesterase (PDE) 111 inhibitor, were studied in five anesthetized bronchoconstricted cats. The animals were challenged by four repeated doses of intratracheal methacholine (67 μg/kg), and the degree of bronchoconstriction was assessed from increases in respiratory system resistance (Rrs). All animals demonstrated good bronchoconstrictive responses (i.e., 86–99% increases in Rrs) to methacholine without tachyphylaxis. On separate day, the cats received the same four doses of methacholine after being pretreated with either intratrachael saline or three different doses of MKS 492 (0.17, 1.7, and 17 μg/kg). The increases in Rrs with 1.7 μg/kg [;52.6 ± 8.4% (SE)] and 17 μg/kg of MKS 492 (44.4 ± 10.1%) were smaller than those with saline pretreatment (88.1 ± 16.8%) (P < 0.05). There were no treatment-associated changes in mean arterial pressure or heart rate during administration of MKS 492. We conclude that intratracheal MKS 492 effectively reduced methacholine-induced bronchoconstriction in dose-dependent fashion without substantial systemic effects. These preliminary results suggest that inhalation of isozyme-selective PDE inhibitors may deserve consideration for clinical trials provided that more extensive preclinical investigations justify such trials. © 1995 Wiley-Liss, Inc.     

Factors that contribute to inhibition of methacholine-induced bronchoconstriction

To evaluate the factors that contribute to inhibition of airways reactivity, we compared the effect of inhaled isoproterenol, 125 micrograms, on the response to methacholine-induced bronchoconstriction in 10 normal and 10 asthmatic subjects. We measured in each subject baseline lung function, response to inhaled bronchodilator, dose of bronchodilator causing 50% maximal response, and degree of airways reactivity to inhalation of methacholine before and after isoproterenol. In asthmatics, but not normal subjects, inhalation of isoproterenol led to significant inhibition of methacholine-induced bronchospasm. In asthmatics, the greater the airways reactivity to methacholine the greater the inhibition by isoproterenol (p less than 0.05). In both groups, there was significant correlation between baseline lung function and level of airways reactivity. In neither normal subjects nor asthmatics did the maximal bronchodilator response to isoproterenol inhalation correlate with inhibition of airways reactivity. Studies evaluating inhibition of airways reactivity should take into account the population tested, baseline lung function, and baseline level of airways reactivity.     

The effect of methacholine inhalation challenge on regional residual volume in patients with subclinical asthma

Regional residual volume to total lung capacity (RVr/TLCr) was measured with xenon 133 before and after methacholine challenge in 26 nonsmoking subjects (mean age 34 years). Eleven were normal control subjects and 15 were patients referred for methacholine challenge because of previous asthma-like symptoms. All had normal pulmonary function and normal RVr/TLCr distribution. Following methacholine challenge, RVr/TLCr increased in two control subjects and ten patients who also had decreases in FEV1 of greater than 20 percent. The RVr/TLCr changes were patchy, suggesting that the degree of bronchospasm varied between individual lung regions. The other 14 subjects did not have a 20 percent decrease in FEV1, but two controls and four patients had generalized increases in RVr/TLCr, while seven controls and one patient had no significant changes in RVr/TLCr. In all subjects, FEV1 and RVr/TLCr returned to the baseline level after salbutamol administration. The results indicate that methacholine can cause localized or diffuse effects on lung emptying and that bronchodilator completely reverses the bronchoconstriction induced by methacholine.     

Continuous versus intermittent nebulization of salbutamol in acute severe asthma: a randomized, controlled trial

STUDY OBJECTIVE: This study was conducted to compare the clinical and spirometric effects of continuous and intermittent nebulization of salbutamol in acute severe asthma. METHODS: Forty-two consecutive patients presenting to the emergency department for acute severe asthma (peak expiratory flow [PEF] mean+/-SD, 24%+/-12% predicted) were prospectively randomly assigned to receive 27.5 mg of salbutamol by either continuous or intermittent nebulization over a 6-hour period. The continuous nebulization group received 15 mg of salbutamol during the first hour and 12.5 mg over the next 5 hours. The intermittent nebulization group received 5 mg of salbutamol every 20 minutes during the first hour and 2.5 mg hourly over the next 5 hours. All participants received oxygen and intravenous hydrocortisone. Clinical and spirometric assessment was performed at baseline, 40 minutes, 60 minutes, and at 3 and 6 hours after the start of the nebulization. Secondary endpoints were the respective rates of hospitalization and treatment failure. RESULTS: A significant clinical and spirometric improvement was observed in both groups over baseline as soon as the 40th minute and was sustained thereafter (absolute PEF increase at the sixth hour 30%+/-18% and 32%+/-22% in the continuous and intermittent nebulization groups, respectively; P <.01 over baseline). PEF and the clinical score evolved similarly in both groups. There was no difference between the groups regarding the failure rate of the initial bronchodilator treatment to terminate the asthma attack (3 [14%] in the continuous nebulization group and 2 [9.5%] in the intermittent nebulization group, absolute difference 4.5% [95% confidence interval -14% to 23%]). Eight (38%) patients and 9 (43%) patients from the continuous and intermittent nebulization groups, respectively, required hospitalization according to predefined criteria (absolute difference 4.8% [95% confidence interval -24% to 34%]). CONCLUSION: We did not observe an appreciable difference between continuous and intermittent nebulization of salbutamol in acute severe asthma. The decision to use one of these nebulization methods should be based on logistical considerations.     

Bronchodilator tolerance: the impact of increasing bronchoconstriction.

Chronic exposure to beta-agonists causes tolerance to their bronchodilator effects, which is best demonstrated during acute bronchoconstriction. The aim of the present study was to assess whether tolerance becomes more evident with increasing bronchoconstriction, as might occur in acute asthma. In a randomised, double-blind, placebo-controlled, crossover study comprising 15 patients, the treatments were salbutamol 400 microg q.i.d. or placebo given via Diskhaler for 28 days with a 2-week washout between treatments. Patients attended on days 14, 21 and 28. Bronchoconstriction was induced on two of these three occasions to achieve a reduction in the forced expiratory volume in one second (FEV1) of 0 (no methacholine), 15 and 30% (using methacholine) in a randomised order. Immediately after this, salbutamol 100 microg, 100 microg and 200 microg was inhaled at 0, 5, and 10 min. FEV1 was measured over 40 min. Dose/response curves were plotted and values for the area under the curve (AUC)0-40 FEV1 were compared between treatments and by degree of bronchoconstriction. Regular salbutamol resulted in attenuation of the acute response to beta-agonist, which was increasingly evident with greater bronchoconstriction. With a reduction in FEV1 of 0, 15 and 30%, the AUC0-40 FEV1 with salbutamol were 11.2, -14.6 and -35.7% respectively, compared to placebo. There was a linear relationship between the magnitude of bronchoconstriction and the between-treatment differences in AUC0-40 FEV1. Increasing bronchoconstriction conferred greater susceptibility to the effects of bronchodilator tolerance.     

Protection Against Exercise-Induced Bronchoconstriction Two Hours After a Single Oral Dose of Montelukast

The objective of this double-blind cross-over study was to evaluate montelukast for the prevention of exercise-induced bronchoconstriction (EIB). Sixty-two patients with EIB (post-exercise decrease in forced expiratory volume in 1 second (FEV₁) ≥ 20% at pre-randomization) were randomized to montelukast 10 mg or placebo, followed by exercise-challenge 2, 12, and 24 hours postdose. The primary endpoint was the maximum percent-fall in FEV₁ (from pre-exercise FEV₁) during 60 minutes after exercise-challenge at 2 hours postdose. This endpoint was improved after montelukast (mean ± SD = 11.7% ± 10.8) versus placebo (17.5% ± 13.8) (p ≤ 0.001); numerically greater improvements were seen at 12 hours and 24 hours. A quicker time to recovery after challenge (p ≤ 0.001) and a smaller area under the curve for percent-fall in FEV₁ during 60 minutes after challenge (p ≤ 0.01) were seen with montelukast at 2 hours. At this timepoint, more patients taking montelukast (45/54) than taking placebo (37/54) were protected against EIB (p = 0.039). We concluded that montelukast provided significant protection against EIB at 2 hours after a single dose.