Standardization of inhalation provocation tests: Influence of nebulizer output,particle size,and method of inhalation

Standardization of inhalation tests requires a knowledge of factors that will affect the response. We measured the output and particle size of six types of nebulizers used for inhalation tests. Output varied considerably between nebulizers of different types (0.12 to 1.59 ml/min) and to a lesser extent between nebulizers of the same type. Particle size varied between 0.8 and 5.2 μm aerodynamic mass median diameter (AMMD). The influence of these two properties on bronchial response to inhaled methacholine was examined. Nebulizer output but not particle size (between 1.3 and 3.6 μm AMMD) altered the response. We also examined the effect of change in inspiratory time during inhalation from residual volume to total lung capacity on lung deposition of radiolabeled aerosol and on the provocative concentration of histamine required to reduce the 1-sec forced expiratory volume (FEV₁) by 20% (PC₂₀). A reduction in inspiratory time from 8 to 2 sec resulted in a lower total lung dose, relatively more aerosol deposited in central airways, and a higher PC₂₀. The results emphasize the importance of keeping nebulizer output and pattern of breathing constant when performing inhalation provocation tests if consistent results are to be obtained.     

The effect of aerosol distribution on airway responsiveness to inhaled methacholine in patients with asthma.

It has been demonstrated that airway deposition of inhaled aerosols is more heterogeneous in patients with asthma than in normal subjects. Nevertheless, the influence of abnormal airway deposition on responses to bronchoactive aerosols is poorly understood. We altered bronchopulmonary deposition heterogeneity of methacholine aerosol in nine asymptomatic patients with asthma by controlling inspiratory flow at high (approximately 60 L/min) versus low (approximately 12 L/min) rates on 2 study days and determined the effect on the provocative dose of methacholine causing a 20% fall in FEV1 (PD20) (often used as a measure of airway responsiveness). Deposition uniformity was quantified from gamma-camera scans of the lungs in terms of the distribution of a technetium-labeled aerosol that was inhaled rapidly or slowly before the inhalation of methacholine. Increased deposition in an inner (large, central airways) versus an outer (peripheral airways and alveoli) zone of the right lung (inner/outer ratio, greater than 1) and higher values of skew (an index of deposition asymmetry) and kurtosis (an index of deposition range) indicated enhanced heterogeneity of deposition. Mean (+/- SD) inner/outer ratio was significantly higher during rapid inspiration compared to slow inspiration with 2.91 +/- 0.51 and 1.84 +/- 0.30, respectively (p less than 0.01). Mean skew and kurtosis were also significantly higher after rapid inspiration, with 1.12 +/- 0.35 and 3.86 +/- 1.25, respectively, compared to 0.74 +/- 0.36 and 2.64 +/- 0.77 after slow inhalation (p less than 0.01). Geometric mean PD20 methacholine was significantly reduced when the aerosol was inhaled rapidly, with 5.9 cumulative methacholine units compared to 15.7 units after slow inhalation (p less than 0.02).(ABSTRACT TRUNCATED AT 250 WORDS)     

Short- and long-term effects of cromolyn sodium on the airway reactivity of asthmatics

To study the effects of cromolyn sodium on the airway reactivity of asthmatics, we performed a randomized, double-blind, crossover study in which 11 atopic asthmatics inhaled 20 mg of cromolyn sodium or a matching placebo four times daily for 4 wk each, while in their allergy season. Bronchial challenges consisting of either eucapnic hyperventilation with frigid air or methacholine were performed before, in the middle, and at the end of each treatment period. Stimulus-response relationships were assessed with the forced expiratory volume in I sec (FEV1). The level of ventilation (VE) and the provocative dose of methacholine (meth) required to reduce the FEV1 20% from control were recorded as the PD20VE and PD20meth, respectively. There were no significant differences in the baseline FEV1 on any study day. The short-term administration of cromolyn brought about a significant increase In PD20VE prior to both the placebo and active phases of the study. Placebo had no effect on airway reactivity. After 2 wk of cromolyn, PD20VE rose significantly and stayed elevated during the course of the study. Neither the short- nor long-term administration of cromolyn had any effect on the responsiveness to methacholine. These results demonstrated that long-term therapy can attenuate the responsiveness to naturally occurring asthmogenic stimuli even when nonspecific reactivity is unchanged.     

Time course of the increase in airway responsiveness associated with late asthmatic reactions to toluene diisocyanate in sensitized subjects

To understand better the mechanism of the increase in airway responsiveness associated with late asthmatic reactions, we determined the time course of toluene diisocyanate (TDI) effect on airway responsiveness in six sensitized subjects who exhibited a late asthmatic response after TDI exposure (0.018 +/- 0.005 ppm, 30 min) in the laboratory. Airway responsiveness was assessed before TDI exposure and then at 8 hr, 1 day, 1 wk, and 1 mo after TDI exposure. To assess responsiveness we determined the provocative dose of methacholine causing a decrease in FEV1 of 20% (PD20FEV1). The methacholine PD20 decreased from 0.50 mg geometric standard error of the mean (GSEM = 1.54) to 0.06 mg (GSEM = 1.55) (p less than 0.001) at 8 hr after exposure to TDI, was still decreased to 0.15 mg (GSEM = 1.93) (p less than 0.05) at 1 day, returned to 0.26 mg (GSEM = 1.91) (p greater than 0.05) at 1 wk, and returned to 0.43 mg (GSEM = 1.71) at 1 mo, indicating that full recovery occurred within 1 to 4 wk. These results demonstrate that TDI-induced late asthmatic response is associated with a reversible increase in airway responsiveness to methacholine and suggest that the TDI effect is linked to an acute inflammatory response in the airways.     

Effects of periodic obstructive apnoeas on superior and inferior venous return in dogs

Obstructive apnoeas could cause flow limitation to venous return, resulting in a decrease in cardiac output and a change in the distribution of flow from the upper and lower body. In 14 anaesthetized dogs, we studied the effects of obstructive apnoeas on inferior and superior vena caval flows under baseline conditions and with intra-abdominal pressure increased by ≈5 torr by binding the abdomen. During obstructive apnoeas in the two groups, respiratory rate decreased by 30% (P < 0.02) and inspiratory airway pressure decreased by ≈15 torr (P < 0.01). At baseline, the ratio of inferior to superior vena caval flow was 2.4:1 and did not change with abdominal binding or apnoeas. During apnoeas there was no change in cardiac output or in the ratio of inferior to superior vena cava flow either with baseline or abdominal binding conditions. Preservation of total inferior vena caval flow during apnoeas and cardiac output occurred, even though inspiratory flow limitation was found with the abdomen bound. We conclude: (1) there was no change in either cardiac output or the distribution of venous return during apnoeas; (2) there was substantial inspiratory/expiratory variation in venous return during obstructive apnoeas. The large inspiratory increase in venous return may have implications for the development of pulmonary hypertension during obstructive apnoeas.     

Airways hyper-responsiveness to bradykinin and methacholine: effects of inhaled fluticasone

BACKGROUND: Although inhaled corticosteroids are the most effective anti-inflammatory agents available for the treatment of asthma, they have, at best, only modest effects on airways responsiveness to methacholine. Thus, hyper-responsiveness to methacholine is a relatively insensitive monitor of the effectiveness of glucocorticoids in asthmatic subjects. OBJECTIVE: The study aimed to determine if airways hyper-responsiveness to bradykinin provides a more sensitive index of glucocorticoid responsiveness in asthmatic subjects than does hyper-responsiveness to methacholine. METHODS: A double-blind, placebo-controlled, parallel group study comparing the effects of inhaled fluticasone (220 micro g twice daily) on responsiveness to the two stimuli in asthmatic subjects who had never previously received corticosteroid therapy. Drug (n = 13) or placebo (n = 12) were administered for 16 weeks. Responsiveness to bradykinin and methacholine was determined at baseline and at 4 week intervals. RESULTS: Placebo did not alter responsiveness to either stimulus compared to baseline. Fluticasone treatment significantly reduced responsiveness to bradykinin (P < 0.001 by Friedman anova) and methacholine (P = 0.02), but changes in responsiveness to bradykinin were significantly greater than those in methacholine responsiveness (P = 0.002). Bradykinin responsiveness was decreased at all treatment times compared to baseline, while methacholine responsiveness was not decreased until 8 weeks of therapy. When data were analyzed as changes from baseline (DeltaLog PD20), DeltaLog PD20 for methacholine was not different at any time-point between the two treatment groups. By contrast, DeltaLog PD20 for bradykinin was significantly greater in patients receiving fluticasone compared to those on placebo at all but the 16-week treatment time. Ten of 13 subjects receiving fluticasone failed, on at least one post-treatment visit, to show a 20% fall in forced expiratory volume (FEV1), even at the highest dose of bradykinin. CONCLUSIONS: Airways responsiveness to bradykinin is more profoundly, and more rapidly, reduced by inhaled glucocorticoids than is responsiveness to methacholine. Airways hyper-responsiveness to bradykinin provides a convenient and sensitive monitor of glucocorticoid responsiveness in asthma.     

The role of 5-lipoxygenase products in the development of airway responsiveness induced by platelet activating factor inhalation in dogs]

To determine whether 5-lipoxygenase products are involved in the development of airway responsiveness and in the infiltration of inflammatory cells into the airway after platelet activating factor (PAF) inhalation, we studied the effect of a selective 5-lipoxygenase inhibitor, AA-861 on PAF-induced airway hyperresponsiveness and on the increase of neutrophil and eosinophil counts in bronchoalveolar lavage fluid (BALF) after PAF inhalation in seven dogs. Airway responsiveness to inhaled methacholine was determined by modified Astograph (7Hz oscillation method). PAF (1000 mu/ml) was delivered as an aerosol, generated from a Devilbiss 646 nebulizer for ten minutes. Airway responsiveness to inhaled methacholine increased significantly 3 hr after PAF inhalation (p less than 0.01). After PAF inhalation, neutrophil and eosinophil counts in BALF increased significantly (p less than 0.01), and the levels of thromboxane (Tx)B2 in BALF also increased (p less than 0.05). Pretreated AA-861 significantly inhibited the increase of airway responsiveness after PAF inhalation (p less than 0.01). The increase of neutrophil and eosinophil counts in BALF after PAF inhalation was also inhibited significantly by pretreated AA-861 (p less than 0.01). The levels of TxB2 in BALF did not change after PAF inhalation following pretreatment with AA-861. These results suggest that 5-lipoxygenase products play important roles in the increase of airway responsiveness and in the infiltration of inflammatory cells into the airway after PAF inhalation in dogs. TxA2 released from inflammatory cells may be involved in the increase of airway responsiveness induced by PAF inhalation.     

Peak expiratory flow variation and bronchial hyperresponsiveness in asthmatic children during periods of antigen avoidance and reexposure

Changes of diurnal variation of peak expiratory flow rate (%PEF variation) and their relationship with bronchial hyperresponsiveness (BHR) to methacholine (PC²⁰) were evaluated in 12 children with mild-to-moderate asthma and house-dust mite allergy, during successive periods of stay in a mite-free environment at high altitude (1756 m) and at their home at sea level. The children remained at the high altitude from October until the end of December; then they spent a 3-week period at home and returned to high altitude residence in January. PEF was measured daily, in the morning and in the evening, during the 3 months' stay at high altitude and then for 10 days after the return in January. PC²⁰ was assessed in 8/12 children, once a month from October to December, and at the return in January. Mean absolute PEF values did not change significantly throughout the study. From October to December, patients showed a significant decrease of mean %PEF variation ( P = 0.04), while PC²⁰ showed an increase ( P = 0.05). After the 3 weeks at home, both %PEF variation ( P = 0.03) and PC²⁰ ( P = 0.05) significantly worsened. The correlation between PC²⁰ values and mean %PEF variation in the 2 days before and after each methacholine test was r =−0.63 ( P = 0.001). Our data suggest that there is a beneficial effect of a prolonged stay in a mite-free environment, on both PEF variability and BHR, also in asthmatic children with good pulmonary function. PEF variability and bronchial responsiveness to methacholine were significantly correlated also for small changes of the two variables.     

Inhaled sodium fluoride decreases airway responsiveness to acetylcholine analogs in vivo

The study was conducted to characterize the action of NaF, which had relaxing property in carbachol precontracted isolated bovine bronchus, on airway responsiveness challenged by acetylcholine receptor agonists in rats and asthmatic humans.Tracheal flow rate and airway resistance were measured in anaesthetized rats. NaF was delivered either before carbachol challenge or together with carbachol. Patients with mild asthma were challenged with methacholine aerosol, and NaF was delivered when FEV1 fell by more than 20%. The results indicated that: (1) in rats NaF significantly inhibited carbachol-induced bronchial constriction when inhaled prior to carbachol challenge as airway resistances in the NaF and NaF+verapamil groups were significantly lower than those in the control group; (2) NaF significantly reversed carbachol or methacholine-induced bronchial constriction in asthmatic patients. In conclusion, NaF, delivered in form of aerosol, reduced bronchial responsiveness to carbachol in rats and had a bronchodilating effect on rat and human airways precontracted by inhalation of acetylcholine analogs.     

Comparison of bronchial responses to prostaglandin F2α and methacholine

We examined bronchial responsiveness to prostaglandin (PG) F_2α to determine its applicability in clinical practice and to compare it with bronchial responsiveness to the pharmacologically dissimilar agent, methacholine. Inhalation tests with twofold increasing concentrations of the two agents were carried out in 19 asthmatic and four normal subjects. The results were expressed as the provocation concentration causing a 20% fall in forced expiratory volume in 1 sec (PC₂₀). The range of concentrations required to determine the PC₂₀ was greater with PGF_2α (0.0001 to <5 mg/ml) than that with methacholine (0.07 to 30.96 mg/ml). Side effects of cough, retrosternal irritation, and expectoration of sputum were more frequent after PGF_2α. Repeat measurements in the same subjects showed that responses to PGF_2α were as highly reproducible (r = 0.98, p < 0.001) as previously reported with methacholine, and there was a cumulative dose effect (p < 0.001). PC₂₀PGF_2α correlated with PC₂₀ methacholine (r = 0.5, p < 0.01), but to a lesser degree than was previously demonstrated between histamine and methacholine. The poorer correlation was explained by the results of four subjects tolerant to PGF_2α relative to methacholine, three of whom were aspirin (ASA) intolerant; the correlation was much stronger when these subjects were excluded from analysis (r = 0.91, p < 0.001). The results suggest that (1) PGF_2α is not a suitable agent to use in clinical practice to measure nonspecific bronchial responsiveness because of the wide dose range and unpleasant side effects, (2) the bronchial responsiveness of different individuals to PGF_2α and methacholine is usually well correlated and is thus unrelated to specific receptor activity, and (3) there is a relative reduction in responsiveness to PGF_2α in some asthmatics, particularly those with ASA intolerance.     

Determinants of airway hyperresponsiveness in mild asthma.

BACKGROUND: Patients with mild asthma may have coexisting severe airway hyperresponsiveness (AHR), although the reasons for this are uncertain. OBJECTIVE: To evaluate the factors that determine AHR in mild asthma. METHODS: We performed a retrospective database evaluation of two groups of patients with mild asthma with forced expiratory volume in 1 second (FEV1) of 80% or more than predicted. Group A (n = 92; mean inhaled corticosteroid dose, 491 microg) had moderate-to-severe AHR to methacholine (provocative dose causing a 20% decrease in FEV1 [methacholine PD20], < or = 100 microg), whereas group B (n = 92; mean inhaled corticosteroid dose, 509 microg) had borderline AHR (methacholine PD20, > or = 800 microg). Both groups were matched for age, sex, inhaled corticosteroid use, and FEV1. RESULTS: From our database, we found 361 patients with an FEV1 of 80% or more than predicted of whom 123 (34%) had a methacholine PD20 of 100 microg or less and 138 (38%) had a methacholine PD20 of 800 microg or more. The methacholine PD20 geometric means (geometric SE) of groups A and B were 25 microg (3 microg) and 5,392 microg (295 microg), respectively. Despite matched mean values for FEV1, compared with group B, group A had a lower predicted forced expiratory flow between 25% and 75% (71% vs 81%, P = 0.007). A greater proportion of group A compared with group B patients were sensitized to house-dust mite (76% vs 54%, P = 0.002). No significant differences were found between groups in terms of presence of rhinitis and sensitization to other individual aeroallergens. CONCLUSIONS: Increased sensitization to house-dust mite and reduced small airway caliber were associated with moderate-to-severe AHR in mild asthma. Skin prick testing to common aeroallergens, especially house-dust mite, should be a routine part in the evaluation of asthmatic patients, including those patients with mild disease.     

The lung parenchymal strip as a model of peripheral airway responsiveness

Twenty-four patients scheduled for surgery for carcinoma of the lung were challenged with inhaled methacholine. A greater than 20% fall in the forced expiratory volume in 1 s (FEV1) was recorded in nine of these patients. The PD20 (dose of methacholine producing a 20% fall in FEV1) values ranged from 0.6 to 5.6 mumol methacholine. Following surgery, lung tissue was prepared as lung parenchymal strips for in vitro studies. There was no correlation between in vivo airway responsiveness to methacholine (PD20) and in vitro sensitivity as measured by the EC50 (the concentration of agonist producing half the maximal tension [Tmax]) for carbachol (r = -0.17; n = 16) or histamine (r = 0.23; n = 24). The variation in in vivo and in vitro responsiveness was not due to the presence of inflammatory cells in the peripheral lung tissue. Of the 38 lung parenchymal strips studied with histamine, 17 demonstrated a variable relaxation response at low concentrations followed by contraction at higher concentrations. The presence or absence of this relaxation response could not be explained in terms of variable proportions of airway or vascular smooth muscle.     

Inspiratory muscle endurance testing: pulmonary ventilation and electromyographic analysis

This study analyzed regional pulmonary ventilation and electromyographic (EMG) activity of the respiratory muscles during an inspiratory muscle endurance (IME) test in 10 young women. Radioaerosol (99mTc-DTPA) was generated using a jet nebulizer connected to a linear inspiratory loading system. The lung scintigraphic analysis showed an increase in the radioaerosol deposition using loads of 20 and 30 cmH(2)O (p<0.01). The vertical gradient showed a larger radioaerosol deposition in the medium third of the lungs during the control period (p<0.001). There were larger amounts of radioaerosol deposition in the medium third when compared with the upper and lower third at 30 cmH(2)O (p<0.001). The horizontal gradient showed a larger deposition in the intermediate and central segments during all phases (p<0.00). Electromyographic activity from the muscles of the lower rib cage increased with loads of 20 and 30 cmH(2)O (p<0.03). There was an increase in deposition of radioaerosol when the load increased (r=0.584, p=0.000 for the left lung and r=0.609, p=0.000 for right lung). These findings suggest that during the IME test, EMG activity in the muscles of the lower rib cage increase during progressive respiratory workloads is associated with a greater radioaerosol deposition in the medium third and intermediate and central segments of the lungs.     

Cromolyn sodium inhibits the increased responsiveness to methacholine that follows ultrasonically nebulized water challenge in patients with asthma

We have previously reported that airway responsiveness to inhaled methacholine in subjects with asthma is increased 40 to 60 minutes after challenge with ultrasonically nebulized water. This study reveals that increased responsiveness to methacholine is abolished by administration of cromolyn sodium before the water challenge. The mean dose of methacholine (95% confidence limits) inducing a 20% fall in FEV1 (PD20) was 1.10 mumol (0.43 to 2.80). The PD20 after water challenge was 0.42 mumol (0.17 to 1.01) that was significantly lower (p less than 0.005) than that observed for the initial challenge. Administration of cromolyn before the water challenge abolished this increased responsiveness to methacholine. The mean PD20 was 1.32 mumol (0.47 to 3.68) that was not significantly different from that measured for the initial methacholine challenge. Methacholine responsiveness was unchanged when challenge was performed 40 to 60 minutes after cromolyn alone or after methacholine itself. We conclude that cromolyn abolishes the increased responsiveness to methacholine and probably does so by inhibiting the release of mediators.     

Methacholine responsiveness increases after ultrasonically nebulized water but not after ultrasonically nebulized hypertonic saline in patients with asthma

Airway obstruction can be induced in patients with asthma by the inhalation of ultrasonically nebulized aerosols of nonisotonic solutions. It is the change in osmolarity of the periciliary fluid that is believed to be the stimulus for bronchoconstriction. However, it is not known whether hyperosmolar and hypo-osmolar aerosols induce asthma via the same mechanism. We have previously reported that patients with asthma have a reduction in the dose of provoking agent that induces a 20% fall in FEV1 (PD20) for methacholine after challenge with nebulized water. To determine whether hyperosmolar aerosols also increase sensitivity to methacholine, we studied 13 subjects with asthma on 3 days. On day 1, the PD20 to methacholine was determined. On day 2, a challenge with nebulized 4.5% saline was followed by a challenge with methacholine 40 to 60 minutes later. On day 3, a challenge with nebulized water was followed by a methacholine challenge. Sensitivity to methacholine was significantly increased after water (p less than 0.02) but not after 4.5% saline. Furthermore, there was no relationship between the PD20 to water and to 4.5% saline. When the Spearman's correlation coefficient was used to compare sensitivity to the challenges, there was a significant relationship between the PD20 to 4.5% saline and methacholine (p less than 0.01) but not between the PD20 to water and methacholine. These results suggest that the mechanism of asthma induced by hyperosmolar and hypo-osmolar solutions is different.     

Comparison of intermittent and continuous inhalation provocation tests

To improve standardization of inhalation provocation tests, two tests utilizing intermittent and continuous inhalation of methacholine aerosol were compared in five normal and ten asthmatic patients. During the intermittent inhalation test, methacholine aerosols with stepwise incremental concentrations were inhaled during tidal breathing for two minutes with a following 5-minute pause interval. Specific airway conductance (SGaw) and respiratory resistance (Rrs) were measured one-half, one and one-half, and five minutes after the end of each inhalation period. Specific airway conductance and Rrs were measured with the panting and forced oscillation methods, respectively. During the continuous inhalation test, the same stepwise incremental concentrations of methacholine aerosol were inhaled during tidal breathing for two minutes without a pause while Rrs was continuously measured. The cumulative dose of methacholine required to reduce SGaw by 35% of the baseline value (PD35 SGaw) during the intermittent inhalation test was significantly correlated with the cumulative methacholine dose required to reduce Grs (= 1/Rrs) by 35% of the baseline value during the continuous inhalation test (PD35 Grs) (r = .98). There was also a significant correlation between the slopes of the intermittent inhalation test and continuous inhalation test curves (r = .80). The results indicate that methacholine provocation can be measured as reliably using a simple continuous inhalation method as by a more complex intermittent one.     

Influence of total IgE and seasonal increase of eosinophil cationic protein on bronchial hyperreactivity in asthmatic grass-sensitized farmers

BACKGROUND: This study correlates biomarkers of atopy (serum total and specific IgE) and inflammation (serum eosinophil cationic protein) with bronchial hyperreactivity assessed after the complete end of pollination, in a group of farmers suffering from grass-allergic asthma. METHODS: A total of 28 asthmatic farmers, with allergy to grass pollen, reporting persistent asthma symptoms after grass pollination, were enrolled. An accurate allergologic screening excluded other sensitizations. Analysis of total and grass-specific IgE and eosinophil cationic protein was carried out before (March) and during (May) the following spring. After the complete end of pollination, bronchial hyperreactivity was assessed. RESULTS: Symptoms (cough, wheezing) persisted during the autumn for a mean period of 41 days (range 13-69). Total IgE was moderately high and grass-specific IgE ranged from 9.25 to 41.12 kU/l without significant differences before and during spring. On the contrary, serum ECP levels significantly increased during the pollination period. PD20 methacholine evaluated after the end of grass pollination was negatively significantly correlated with levels of total IgE (r=-0.73; P<0.01) and the increase (from March to May) of serum ECP (r=-0.75; P<0.01). However, PD20 methacholine did not correlate with grass-specific IgE and serum ECP absolute values of both March and May. A positive correlation was found between number of postseasonal days with symptoms and both spring increase of serum ECP (r=0.75; P=0.04) and levels of total IgE (r=0.76; P<0.01). The number of postseasonal days with symptoms inversely correlated with postseason PD20 methacholine (r=-0.76; P<0.01). CONCLUSIONS: The study demonstrates that in grass-sensitized farmers with asthmatic symptoms persisting for several weeks after grass pollination has ceased, the degree of airways hyperreactivity and the duration of postseasonal symptoms are directly related to the spring increase of ECP levels, as well as to the level of total IgE in serum. This allows us to identify two candidate biomarkers for the risk of developing prolonged asthma symptoms, and for the effective monitoring of anti-inflammatory treatment and allergen-specific immunotherapy.     

Effect of omalizumab on adenosine 5'-monophosphate responsiveness in subjects with allergic asthma

BACKGROUND: The objective of this study was to evaluate the effects of omalizumab on bronchoconstriction induced by methacholine and adenosine 5'-monophosphate (AMP). METHODS: Thirty-four subjects with mild to moderate allergic asthma were randomized to receive placebo (n = 16) or omalizumab (n = 18) subcutaneously during 12 weeks. Airway responsiveness to AMP was measured at baseline and after 4 and 12 weeks of treatment, whereas the response to methacholine was measured at baseline and after 12 weeks of treatment. RESULTS: After 4 weeks of treatment, the increase in AMP PC(20) (provocative concentration required to produce a 20% fall in FEV(1)) was significantly greater in the omalizumab group than in the placebo group, the mean difference in the change between the groups being 1.52 doubling concentrations (95% CI, 0.25-2.79, p = 0.02). Compared with baseline, the mean AMP PC(20) values at 12 weeks were increased by 1.91 doubling concentrations with omalizumab (p < 0.001) and 1.01 doubling concentrations with placebo (p = 0.16), but changes were not significantly different between the treatment groups. Changes in methacholine PC(20) values were not significantly different between the omalizumab and placebo groups. CONCLUSIONS: In subjects with allergic asthma, omalizumab reduces the response to AMP without decreasing the response to methacholine. These findings are consistent with the conclusion that the contribution of IgE to the development of AMP bronchoconstriction is more important than their role in the induction of methacholine hyperresponsiveness.     

Relationship between bronchial responsiveness to hyperventilation with cold and methacholine in asthma

Twenty-seven subjects with asthma and normal baseline lung function were challenged with aerosols of methacholine (M) and by isocapnic hyperventilation with cold air (HV). Stimulus-effect relationships were determined for each provocational technique on separate days and were expressed as the dose required to produce a 20% fall in forced expired volume in 1 sec (FEV₁) obtained by linear interpolation from log stimulus vs. response curves (PD₂₀). Each stimulus was applied with a sufficient intensity to produce a 20% or greater fall in FEV₁ in each subject. The PD₂₀ for M correlated significantly with the PD₂₀ for HV (p < 0.001) when the latter was expressed in liters per minute. The correlation between cumulative M PD₂₀ and HV PD₂₀ expressed as a percent of maximal voluntary ventilation was significant but less strong. We conclude that the airway response to HV reflects nonspecific bronchial hyperresponsiveness and that the dose of HV is best determined as the absolute level of ventilation.     

Effect of inspiratory muscle work on peripheral fatigue of locomotor muscles in healthy humans

The work of breathing required during maximal exercise compromises blood flow to limb locomotor muscles and reduces exercise performance. We asked if force output of the inspiratory muscles affected exercise-induced peripheral fatigue of locomotor muscles. Eight male cyclists exercised at ≥ 90% peak O₂ uptake to exhaustion (CTRL). On a separate occasion, subjects exercised for the same duration and power output as CTRL (13.2 ± 0.9 min, 292 W), but force output of the inspiratory muscles was reduced (−56% versus CTRL) using a proportional assist ventilator (PAV). Subjects also exercised to exhaustion (7.9 ± 0.6 min, 292 W) while force output of the inspiratory muscles was increased (+80% versus CTRL) via inspiratory resistive loads (IRLs), and again for the same duration and power output with breathing unimpeded (IRL-CTRL). Quadriceps twitch force ( Q _tw), in response to supramaximal paired magnetic stimuli of the femoral nerve (1–100 Hz), was assessed pre- and at 2.5 through to 70 min postexercise. Immediately after CTRL exercise, Q _tw was reduced −28 ± 5% below pre-exercise baseline and this reduction was attenuated following PAV exercise (−20 ± 5%; P < 0.05). Conversely, increasing the force output of the inspiratory muscles (IRL) exacerbated exercise-induced quadriceps muscle fatigue ( Q _tw=−12 ± 8% IRL-CTRL versus −20 ± 7% IRL; P < 0.05). Repeat studies between days showed that the effects of exercise per se , and of superimposed inspiratory muscle loading on quadriceps fatigue were highly reproducible. In conclusion, peripheral fatigue of locomotor muscles resulting from high-intensity sustained exercise is, in part, due to the accompanying high levels of respiratory muscle work.