Impact of obesity on the severity and therapeutic responsiveness of acute episodes of asthma.

BACKGROUND: It has been suggested that obesity adversely influences both the severity and the therapeutic responsiveness of chronic asthma. However, it is unclear if it also impacts acute situations. METHODS: To determine whether adiposity worsens the clinical and physiological manifestations of acute asthma and limits therapeutic effectiveness of standard treatment, we contrasted signs, symptoms, medication use, arterial oxygen saturation, peak expiratory flow rate, and the bronchodilator response to standard doses of albuterol in 90 non-obese and 90 obese asthmatics as they presented for urgent care. Treatment and clinical decisions were systematized using published care paths and the peak flow was measured with standard techniques. Body mass index (BMI) was calculated according to consensus criteria. RESULTS: Other than BMI (p < .001), there were no between-group differences in age, gender, race, signs, symptoms, pulse oximetry, or pre-presentation medication use. The pretreatment peak flow in the obese population was 22.4% higher on average (p = .007), but there were no differences in the distribution of severity (p = .38), the response to albuterol (p = .61), or admission-discharge ratios (p = .62). CONCLUSIONS: Obesity does not adversely influence the severity or the resolution of acute episodes of asthma.

Critical comparisons of the clinical performance of oxygen-conserving devices.

RATIONALE: Clinical testing of oxygen-conserving devices is not mandated before marketing. Consequently, little is known about individual or comparative therapeutic effectiveness. OBJECTIVES: To relate oxygen delivery from prototypical instruments to physiological performance. METHODS: Thirteen subjects with obstructive lung disease performed progressive treadmill exercise while inhaling either room air, 2 L O(2)/min, or bolus oxygen from four commercially available conserving devices at regulator settings of 2, 5, and continuous. The devices were studied blindly in random order after first being tested to determine performance characteristics. Pulse oximetry, oxygen delivery, and nasal and oral ventilations were monitored at rest and with exertion. MEASUREMENTS AND MAIN RESULTS: At a setting of 2 at rest, all conservers maintained saturation greater than 90%, but there were significant differences in oxygenation between systems. Only one equaled 2 L O(2)/min. With exertion, saturation decreased with all conservers but not with 2 L O(2)/min. One device did not perform any better than room air. Two systems provided less oxygen than predicted, one more, and in one the expected and actual amounts were equal only at rest. Breath-by-breath performance was highly variable, with irregular activation and inconsistent oxygen bolus size delivery. Increasing oxygen pulse volume to the point of eradicating conservation with the continuous setting did not eliminate all disparities. CONCLUSIONS: The mechanical and clinical performances of current oxygen conservers are highly variable and in some instances actually contribute to limitations in exercise ability. Seemingly equivalent technical features do not guarantee equivalent therapeutic functionality.

Safety of binodenoson, a selective adenosine A2A receptor agonist vasodilator pharmacological stress agent, in healthy subjects with mild intermittent asthma.

BACKGROUND: The pharmacological stress agents adenosine and dipyridamole are contraindicated in asthma patients because of the risk of adenosine receptor-mediated bronchospasm. Binodenoson, a selective adenosine A(2A) receptor agonist, produces maximal coronary hyperemia during pharmacological stress testing yet has a low affinity for the adenosine A(1), A(2B), and A(3) receptors that are probably responsible for bronchospasm. This study was conducted to assess the safety of binodenoson in 87 healthy young adult volunteers with documented mild, intermittent asthma. METHODS AND RESULTS: This study consisted of a dose-escalating, single-blinded phase and a placebo-controlled, double-blinded phase conducted in healthy, young adults with documented mild, intermittent, asthma. In the single-blinded phase, 3 sequential cohorts of 8 subjects received intravenous binodenoson (0.5, 1.0, and 1.5 microg/kg). In the double-blinded phase, commenced after medical review of results from the single-blinded phase, subjects were randomly assigned 2:1 to either binodenoson 1.5 microg/kg (n=41) or placebo (n=22). The primary end point was clinically significant bronchoconstriction, defined as a decrease in forced expiratory volume in 1 second of >/=20% from the preinjection measure. Secondary safety end points were changes from preinjection measure in forced expiratory volume in 1 second, forced vital capacity, and forced expiratory flow during the middle 50% of the forced vital capacity; vital signs; pulse oximetry; and adverse events. Binodenoson caused no clinically significant bronchoconstriction or alterations in pulmonary function parameters and transiently increased heart rate and systolic blood pressure. The most common treatment-emergent adverse events were tachycardia, dizziness, and flushing. CONCLUSIONS: Binodenoson was safe, well tolerated, and caused no clinically significant bronchoconstriction or pulmonary responses in a small population of healthy subjects with mild, intermittent asthma.

Observations on the physiological interactions between obesity and asthma.

To explore whether asthma and obesity share overlapping pathogenic features, we examined the impact of each alone, and in combination, on multiple aspects of lung function. We reasoned that if they influenced the lungs through similar mechanisms, the individual physiological manifestations in the comorbid state should interact in a complex fashion. If not, then the abnormalities should simply add. We measured specific conductance, spirometry, lung volumes, and airway responsiveness to adrenergic and cholinergic agonists in 52 normal, 53 asthmatic, 52 obese, and 53 asthmatic and obese patients using standard techniques. Six-minute walks were performed in subsets from each group. Asthma significantly lowered specific conductance and the spirometric variables while increasing airway reactivity and residual volume. Obesity also reduced the spirometric variables as well as total lung capacity and functional residual capacity. Residual volume, specific conductance, and airway responsivity were unaltered. With comorbidity, the disease-specific derangements added algebraically. Features that existed in isolation appeared unchanged in the combination, whereas shared ones either added or subtracted depending on the individual directional changes. Synergistic interactions were not observed. Body mass index weakly correlated with spirometry and lung volumes in asthma, but not with specific conductance or bronchial reactivity. Exercise performance did not aid in differentiation. Our findings indicate asthma and obesity appear to influence the respiratory system through different processes.

Validating a guidelines based asthma decision support system: step one.

Purpose. To quantify the accuracy of a computerized decision support system in discerning severe asthma in a clinical setting. Design. A total of 69 consecutive asthmatics examined in an asthma clinic were classified as "severe" or "mild" by the computerized decision support system and expert asthma clinicians. The expert asthma clinicians were the reference standard. Results. The accuracy was 91%, the sensitivity 96%, the specificity 73%, the positive predictive value 93%, and the negative predictive value 85%. Conclusions. The asthma decision support system was able to discern "mild" from "severe" asthma in a similar fashion to expert asthma clinicians.

Impact of race on the severity of acute episodes of asthma and adrenergic responsiveness.

RATIONALE: African Americans acutely ill with asthma come to emergency departments more frequently and are admitted to hospital more often than whites but the reasons are unclear. OBJECTIVES: To determine whether such phenomena represent racial differences in attack severity or limited effectiveness of beta(2)-agonist therapy. METHODS AND MAIN RESULTS: We contrasted clinical features, airflow limitation, and albuterol responsiveness in adults acutely ill with asthma, 155 of whom where African American and 140 white, as they presented to eight emergency departments. Assessments were standardized across institutions using a care path, and admission and discharge decisions were made according to predetermined criteria. The degree of obstruction was measured by peak expiratory flow rates. The clinical features of both groups were similar. The African Americans, however, had lower flow rates (p = 0.002), and more of them experienced severe or potentially life threatening episodes (p < 0.001). Albuterol was equally efficacious in both populations and there were no differences in the post-treatment flow rates achieved irrespective of the initial attack intensity. There were no racial differences in admission/discharge ratios. CONCLUSIONS: Our data indicate that African Americans with asthma tend to present with somewhat more intense attacks than whites, but they respond equally well to routine treatment. Similarly, there were no racial disparities in hospitalizations when standard criteria are employed.

The effects of hyperpnea on exhaled nitric oxide synthesis in normal subjects.

STUDY OBJECTIVES: To determine if the concentration of nitric oxide (NO) in the lungs increases with hyperpnea by contrasting calculated production (ie, the product of the fractional expired NO concentration [FeNO] and minute ventilation [Ve]) [Vno] with the amount of NO in equilibrium with the conducting airways (eNOair) and the amount of NO diffusing from the alveoli (eNOalv). DESIGN: Observational study. SETTING: University teaching hospital. PARTICIPANTS: Normal subjects. INTERVENTIONS: Measurements were made in 16 healthy people during and after 4 min of tidal breathing (10 L/min) and isocapnic hyperventilation of 60 L/min. MEASUREMENTS AND RESULTS: FeNO was measured by collecting the exhaled air during the last minute of each trial and passing it through a chemiluminescence analyzer. The expired NO levels in the plateau phases of slow (30 mL/s) and fast (200 mL/s) single-breath exhalations were also obtained before and after hyperventilation. The Vno (mean +/- SEM) increased from 89.8 +/- 12.3 to 329.1 +/- 36.2 nL/min as Ve rose (p < 0.001). However, neither the quantities of eNOair nor eNOalv changed with hyperventilation (eNOair range before to after, 34.9 +/- 7.7 to 30.9 +/- 6.4 parts per billion [ppb], p = 0.96; eNOalv range before to after, 7.3 +/- 1.5 to 6.5 +/- 1.1 ppb, p = 0.97). CONCLUSIONS: These data demonstrate that the amount of NO in equilibrium with the airway walls and alveoli are not altered by hyperpnea. Rather, the apparent augmentation in Vno in such circumstances appears to be an arithmetic artifact.

Bronchoprotective effects of single doses of salmeterol combined with montelukast in thermally induced bronchospasm.

STUDY OBJECTIVES: Salmeterol (S) and montelukast (M) individually inhibit the obstructive consequences of thermal stimuli such as exercise and hyperventilation (HV), but there is no information on whether these drugs can interact positively. DESIGN: Randomized trial. SETTING: University teaching hospital. PARTICIPANTS: Atopic asthmatic patients with sensitivity to thermal provocations. INTERVENTIONS: Eleven asthmatic patients generated stimulus-response curves to isocapnic HV while breathing frigid air without any interventions and then after pretreatment with 42 mug of S, 10 mg of M, and the combination. The order of testing was randomly determined. MEASUREMENTS AND RESULTS: Minute ventilation (Ve) was increased in 20-L increments until FEV(1) fell >or= 15%. Measurements were obtained before and 1 h after drug administration, and then again 5 min after each bout of HV. In the nonintervention trial, the provocation commenced after the patients presented to the laboratory. In the control challenge, the mean (+/- SEM) FEV(1) decreased 24.6 +/- 1.7% from baseline. S and M both increased the mean prechallenge FEV(1) significantly (S, 10.4 +/- 1.7% [p < 0.01]; M, 4.1 +/- 1.3% [p = 0.02]; S + M, p = 0.01). The combination of S + M produced greater bronchodilatation (mean improvement, 12.4 +/- 2.3%) than M alone (p = 0.004), but not greater than S alone (p = 0.80). Both drugs blunted the obstructive response similarly (protection: M, 34.6 +/- 15.1%; S, 60 +/- 8.7%; p = 0.13). The benefits added arithmetically with the combined regimen (protection with S + M, 84.9 +/- 5.5%; p = 0.01 vs S alone; p = 0.003 vs M alone). CONCLUSION: These data indicate that the concurrent administration of single standard doses of S and M appears to provide greater protection against thermal stimuli than does either drug alone. Further experimentation will be required to ascertain whether the combination will provide additional clinical benefits to patients over those of the single agents.

Morphometric changes after thermal and methacholine bronchoprovocations.

To determine whether there are distinctions in the location and pattern of response between different bronchoprovocations, we performed high-resolution computer-assisted tomography in 10 asthmatic subjects before and after isocapnic hyperventilation of frigid air (HV) and methacholine (Meth). The luminal areas of the trachea, main stem, lobar, and segmental bronchi were computed before and after each provocation and blindly compared. Both stimuli reduced the 1-s forced expiratory volume similarly (percent change in 1-s forced expiratory volume HV = 28.1 +/- 5.5%, Meth = 25.8 +/- 5.2%; P = 0.69) but did so in different fashions. Each provocation was associated with the development of both bronchial narrowing and dilation; however, more airways constricted with HV (67.7%) than with Meth (47.0%; P < 0.001). Furthermore, there was little concordance between either the magnitude or direction of change between stimuli in any region of the lung (r = 0.25). In general, the frequency of narrowing increased with branching. Constriction became more prominent in the lobar regions and increased further in the segmental branches, but a wide range of intensity existed. These data demonstrate that provocational stimuli evoke complex morphometric changes within the tracheobronchial tree and that different agonists produce different patterns. Thermal stimuli chiefly influence the segmental level, whereas the response to Meth develops more distally. Even within this distribution, the same airway does not respond in an identical fashion to different stimuli, so there does not appear to be a uniform trigger zone.

Acute severe asthma.

Acute severe asthma remains a major economic and health burden. The natural history of acute decompensations is one of resolution and only about 0.4% of patients succumb overall. Mortality in medical intensive care units is higher but is less than 3% of hospital admissions. "Near-fatal" episodes may be more frequent, but precise figures are lacking. However, about 30% of medical intensive care unit admissions require intubation and mechanical ventilation with mortality of 8%. Morbidity and mortality increase with socioeconomic deprivation and ethnicity. Seventy to 80% of patients in emergency departments clear within 2 hours with standardized care. The relapse rate varies between 7 and 15%, depending on how aggressively the patient is treated. The airway obstruction in the 20-30% of people resistant to adrenergic agonists in the emergency department slowly reverses over 36-48 hours but requires intense treatment to do so. Current therapeutic options for this group consist of ipratropium and corticosteroids in combination with beta2 selective drugs. Even so, such regimens are not optimal and better approaches are needed. The long-term prognosis after a near-fatal episode is poor and mortality may approach 10%.

Desiccation and hypertonicity of the airway surface fluid and thermally induced asthma.

To determine whether drying and hypertonicity of the airway surface fluid (ASF) are involved in thermally induced asthma, nine subjects performed isocapnic hyperventilation (HV) (minute ventilation 62.2 +/- 8.3 l/min) of frigid air (-8.9 +/- 3.3 degrees C) while periciliary fluid was collected endoscopically from the trachea. Osmolality was measured by freezing-point depression. The baseline 1-s forced expiratory volume was 73 +/- 4% of predicted and fell 26.4% 10 min postchallenge (P > 0.0001). The volume of ASF collected was 11.0 +/- 2.2 microl at rest and remained constant during and after HV as the airways narrowed (HV 10.6 +/- 1.9, recovery 6.5 +/- 1.7 microl; P = 0.18). The osmolality also remained stable throughout (rest 336 +/- 16, HV 339 +/- 16, and recovery 352 +/- 19 mosmol/kgH(2)O, P = 0.76). These data demonstrate that airway desiccation and hypertonicity of the ASF do not develop during hyperpnea in asthma; therefore, other mechanisms must cause exercise- and hyperventilation-induced airflow limitation.

Influence of hyperpnea on airway surface fluid volume and osmolarity in normal humans.

To determine the effect of hyperpnea on the characteristics of periciliary liquid, we collected airway surface fluid (ASF) and measured its osmolarity in 11 normal people while they breathed dry, frigid air (-17 +/- 1.2 degrees C) at minute ventilations (VE) of 10, 40, and 80 l/min through a heat exchanger. The ASF was collected at the fifth tracheal ring by absorption onto filter paper pledgets inserted via fiber-optic bronchoscopy. Hyperpnea had no influence on the amount of ASF recovered (ASF volume at a VE of 10 l/min = 12.0 +/- 2.0 microl; at 80 l/min = 8.8 +/- 1.5 microl; P = 0.28) or its osmolarity (at a VE of 10, 40, and 80 l/min = 326 +/- 15, 323 +/- 11, and 337 +/- 12 mosM, respectively; P = 0.65). These findings demonstrate that the tracheal mucosa of normal subjects does not dessicate during hyperpnea and that hypertonicity of the periciliary fluid does not develop even at high levels of ventilation.

Inhibition of nitric oxide synthesis attenuates thermally induced asthma.

To determine whether the inhibition of nitric oxide (NO) synthesis attenuates thermally induced obstruction, we had 10 asthmatic volunteers perform isocapnic hyperventilation with frigid air after inhaling 1 mg of N(G)-monomethyl-L-arginine (L-NMMA) or isotonic saline in a blinded fashion. The challenges were identical in all respects, and there were no differences in baseline lung function [1-s forced expiratory volume (FEV(1)); saline 2.8 +/- 0.3 liters, L-NMMA 2.9 +/- 0.3 liters; P = 0.41] or prechallenge fractional concentration of nitric oxide in the exhaled air (FENO) [saline 23 +/- 6 parts/billion (ppb), L-NMMA 18 +/- 4 ppb; P = 0.51]. Neither treatment had any impact on the FEV(1), pulse, or blood pressure. After L-NMMA, FENO fell significantly (P < 0.0001), the stimulus-response curves shifted to the right, and the minute ventilation required to reduce the FEV(1) 20% rose 53.5% over control (P = 0.02). The results of this study demonstrate that NO generated from the airways of asthmatic individuals may play an important role in the pathogenesis of thermally induced asthma.

Exhaled nitric oxide and thermally induced asthma.

The purpose of the present study was to determine if nitric oxide (NO) is involved in the pathogenesis of thermally induced asthma. To provide data on this issue, 10 normal and 13 asthmatic subjects performed isocapnic hyperventilation with frigid air while the fractional concentration of NO in the expirate air (FENO) was serially monitored with a chemiluminescence analyzer. FEV1 was measured before and after hyperpnea. Prior to and throughout the challenge, the asthmatics had significantly larger values for FENO (baseline FENO normal, 11 +/- 2 ppb; asthma, 16 +/- 1; p = 0.03). Posthyperpnea, the normal subjects had little change in bronchial caliber (deltaFEV1 baseline to 5 min posthyperpnea, -3.5 +/- 1.5%; p = 0.06), whereas the patients with asthma developed significant airway obstruction (deltaFEV1, -27.7 +/- 2.9%; p = 0.0001). During hyperventilation, the volume of NO rose in both groups. The asthmatic subjects, however, generated approximately 55% more NO/min than did the normal control subjects even though their level of ventilation was approximately 66% less. In contrast to the normal subjects, NO production in the asthmatics continued into the recovery period after the challenge stopped and FENO rose temporally as the airflow limitation developed. These results suggest that NO plays an intimate role in the development of airway obstruction that follows hyperpnea.

Comparative effects of long-acting beta2-agonists, leukotriene receptor antagonists, and a 5-lipoxygenase inhibitor on exercise-induced asthma.

BACKGROUND: Exercise-induced asthma (EIA) is a common problem that can be controlled with long-acting beta-agonists and leukotriene-modifying compounds. There is, however, limited information on the comparative effectiveness of the two classes of drugs, as well as the relative potencies of the antileukotriene agents. OBJECTIVE: The purpose of the present study was to provide data on the above issues. METHODS: We performed a random-order, blinded, double-dummy, placebo-controlled trial in 10 patients with EIA. Each subject received standard single doses of salmeterol, montelukast, zafirlukast, zileuton, and placebo on separate days. The participants performed 4 minutes of cycle ergometry while breathing frigid air 1, 4, 8, and 12 hours after administration of the test agents. The primary endpoint was the extent of the decrement in the FEV(1) 10 minutes after exertion. RESULTS: With placebo, symptomatic airway narrowing developed at all times (mean +/- SE decrease in FEV(1) ranged between 21% +/- 5% and 26% +/- 5%). Salmeterol acted quickly and significantly blunted the obstructive response for 12 hours (DeltaFEV(1) first hour: 8% +/- 3%; DeltaFEV(1) twelfth hour: 8% +/- 3%; P <.0001 vs placebo and P =.72 vs time). The leukotriene-modifying agents produced effects within 1 hour of ingestion. Like salmeterol, montelukast and zafirlukast also offered long-lasting protection, and there were no significant differences between them (montelukast DeltaFEV(1) twelfth hour: 9% +/- 4%; zafirlukast DeltaFEV(1) twelfth hour: 11% +/- 2%; P =.75) or the beta(2)-agonist (montelukast vs salmeterol: P =.72; zafirlukast vs salmeterol: P =.48). Zileuton provided equivalent prophylaxis for the first 4 hours (DeltaFEV(1) fourth hour: 11% +/- 2%); however, by 8 hours, it was less efficacious than all of the other active compounds, and by 12 hours it did not differ from placebo (DeltaFEV(1) twelfth hour: 19% +/- 4%; P =.33). CONCLUSIONS: Single doses of the currently available leukotriene receptor antagonists provide prompt effective and persistent defense against EIA that equals that seen with a long-acting beta(2)-agonist. The synthesis inhibitor zileuton affords a comparable magnitude of prophylaxis but has a considerably shorter duration of action.